Protease Inhibitors for the Treatment of HIV/AIDS: Recent Advances and Future Challenges

Chandrashekhar       Voshavar
doi:10.2174/1568026619666190619115243
Abstract

Acquired Immunodeficiency Syndrome (AIDS) is a chronic disease characterized by multiple life-threatening illnesses caused by a retro-virus, Human Immunodeficiency Virus (HIV). HIV infection slowly destroys the immune system and increases the risk of various other infections and diseases. Although, there is no immediate cure for HIV infection/AIDS, several drugs targeting various cruxes of HIV infection are used to slow down the progress of the disease and to boost the immune system. One of the key therapeutic strategies is Highly Active Antiretroviral Therapy (HAART) or ' AIDS cocktail' in a general sense, which is a customized combination of anti-retroviral drugs designed to combat the HIV infection. Since HAART’s inception in 1995, this treatment was found to be effective in improving the life expectancy of HIV patients over two decades. Among various classes of HAART treatment regimen, Protease Inhibitors (PIs) are known to be widely used as a major component and found to be effective in treating HIV infection/AIDS. For the past several years, a variety of protease inhibitors have been reported. This review outlines the drug design strategies of PIs, chemical and pharmacological characteristics of some mechanism-based inhibitors, summarizes the recent developments in small molecule based drug discovery with HIV protease as a drug target. Further discussed are the pharmacology, PI drug resistance on HIV PR, adverse effects of HIV PIs and challenges/impediments in the successful application of HIV PIs as an important class of drugs in HAART regimen for the effective treatment of AIDS.
Keywords: Acquired immunodeficiency syndrome, Human immunodeficiency virus, Protease inhibitors, Antiretroviral drugs, Drug discovery, AIDS therapy.
« Previous Next »
Graphical Abstract

[1] 
 Global HIV & AIDS statistics-2018 fact sheet, 2018. (Available at:. http://www.unaids.org
[2] 
Centers for Disease Control and Prevention (CDC). HIV surveillance report: Diagnoses of HIV Infection in the United States and dependent areas. https://www.cdc.gov/hiv/library/reports/hiv-surveillance.html (Accessed 2017).
[3] 
Gallo, R.C.; Salahuddin, S.Z.; Popovic, M.; Shearer, G.M.; Kaplan, M.; Haynes, B.F.; Palker, T.J.; Redfield, R.; Oleske, J.; Safai, B. Frequent detection and isolation of cytopathic retroviruses (HTLV-III) from patients with AIDS and at risk for AIDS. Science,  1984, 224(4648), 500-503.
[http://dx.doi.org/10.1126/science.6200936] [PMID:  6200936] 
[4] 
Levy, J.A.; Hoffman, A.D.; Kramer, S.M.; Landis, J.A.; Shimabukuro, J.M.; Oshiro, L.S. Isolation of lymphocytopathic retroviruses from San Francisco patients with AIDS. Science,  1984, 225(4664), 840-842.
[http://dx.doi.org/10.1126/science.6206563] [PMID:  6206563] 
[5] 
Gowda, S.D.; Stein, B.S.; Mohagheghpour, N.; Benike, C.J.; Engleman, E.G. Evidence that T cell activation is required for HIV-1 entry in CD4+ lymphocytes. J. Immunol.,  1989, 142(3), 773-780.
[PMID:  2521508] 
[6] 
Michie, C.A. Recent developments in theories of pathogenesis of AIDS. Trends Microbiol.,  1996, 4(8), 299.
[http://dx.doi.org/10.1016/0966-842X(96)81547-2] [PMID:  8856865] 
[7] 
Antia, R.; Halloran, M.E. Recent developments in theories of pathogenesis of AIDS. Trends Microbiol.,  1996, 4(7), 282-285.
[http://dx.doi.org/10.1016/0966-842X(96)10044-5] [PMID:  8829337] 
[8] 
Frankel, A.D.; Young, J.A. HIV-1: Fifteen proteins and an RNA. Annu. Rev. Biochem.,  1998, 67, 1-25.
[http://dx.doi.org/10.1146/annurev.biochem.67.1.1] [PMID:  9759480] 
[9] 
Rodríguez-Barrios, F.; Gago, F. HIV protease inhibition: Limited recent progress and advances in understanding current pitfalls. Curr. Top. Med. Chem.,  2004, 4(9), 991-1007.
[http://dx.doi.org/10.2174/1568026043388529] [PMID:  15134553] 
[10] 
Huang, L.; Chen, C. Understanding HIV-1 protease autoprocessing for novel therapeutic development. Future Med. Chem.,  2013, 5(11), 1215-1229.
[http://dx.doi.org/10.4155/fmc.13.89] [PMID:  23859204] 
[11] 
Huff, J.R. HIV protease: A novel chemotherapeutic target for AIDS. J. Med. Chem.,  1991, 34(8), 2305-2314.
[http://dx.doi.org/10.1021/jm00112a001] [PMID:  1875332] 
[12] 
Wlodawer, A.; Erickson, J.W. Structure-based inhibitors of HIV-1 protease. Annu. Rev. Biochem.,  1993, 62, 543-585.
[http://dx.doi.org/10.1146/annurev.bi.62.070193.002551] [PMID:  8352596] 
[13] 
Tomasselli, A.G.; Heinrikson, R.L. Targeting the HIV-protease in AIDS therapy: A current clinical perspective. Biochim. Biophys. Acta,  2000, 1477(1-2), 189-214.
[http://dx.doi.org/10.1016/S0167-4838(99)00273-3] [PMID:  10708858] 
[14] 
Lebon, F.; Ledecq, M. Approaches to the design of effective HIV-1 protease inhibitors. Curr. Med. Chem.,  2000, 7(4), 455-477.
[http://dx.doi.org/10.2174/0929867003375146] [PMID:  10702619] 
[15] 
 US FDA. Antiretroviral drugs used in the treatment of HIV infection., https://www.fda.gov/patients/hivtreatment/antiretroviral-drugs-used-treatment-hiv-infection (Accessed 2018).
[16] 
Arts, E.J.; Hazuda, D.J. HIV-1 antiretroviral drug therapy. Cold Spring Harb. Perspect. Med.,  2012, 2(4)a007161
[http://dx.doi.org/10.1101/cshperspect.a007161] [PMID:  22474613] 
[17] 
Konstantinov, I.; Stefanov, Y.; Kovalevsky, A.; Voronin, Y. Science,  2011, 331(6019), 848-849.
[http://dx.doi.org/10.1126/science.331.6019.848] 
[18] 
Lu, D.Y.; Wu, H.Y.; Yarla, N.S.; Xu, B.; Ding, J.; Lu, T.R. HAART in HIV/AIDS Treatments: Future trends. Infect. Disord. Drug Targets,  2018, 18(1), 15-22.
[http://dx.doi.org/10.2174/1871526517666170505122800] [PMID:  28474549] 
[19] 
Seitz, R. Human immunodeficiency virus (HIV). Transfus. Med. Hemother.,  2016, 43(3), 203-222.
[http://dx.doi.org/10.1159/000445852] [PMID:  27403093] 
[20] 
Goodsell, D.S. Illustrations of the HIV life cycle. Curr. Top. Microbiol. Immunol.,  2015, 389, 243-252.
[http://dx.doi.org/10.1007/82_2015_437] [PMID:  25716304] 
[21] 
Nisole, S.; Saïb, A. Early steps of retrovirus replicative cycle. Retrovirology,  2004, 1, 9.
[http://dx.doi.org/10.1186/1742-4690-1-9] [PMID:  15169567] 
[22] 
Kurapati, K.R.; Samikkannu, T.; Atluri, V.S.; Nair, M.P. Cell cycle checkpoints and pathogenesis of HIV-1 infection: A brief overview. J. Basic Clin. Physiol. Pharmacol.,  2015, 26(1), 1-11.
[http://dx.doi.org/10.1515/jbcpp-2014-0018] [PMID:  25046311] 
[23] 
Wilen, C.B.; Tilton, J.C.; Doms, R.W. HIV: Cell binding and entry. Cold Spring Harb. Perspect. Med.,  2012, 2(8)a006866
[http://dx.doi.org/10.1101/cshperspect.a006866] [PMID:  22908191] 
[24] 
Menéndez-Arias, L. Special issue: Retroviral enzymes. Viruses,  2010, 2(5), 1181-1184.
[http://dx.doi.org/10.3390/v2051181] [PMID:  21994674] 
[25] 
Desfarges, S.; Ciuffi, A. Retroviral integration site selection. Viruses,  2010, 2(1), 111-130.
[http://dx.doi.org/10.3390/v2010111] [PMID:  21994603] 
[26] 
Isel, C.; Ehresmann, C.; Marquet, R. Initiation of HIV reverse transcription. Viruses,  2010, 2(1), 213-243.
[http://dx.doi.org/10.3390/v2010213] [PMID:  21994608] 
[27] 
Skalka, A.M.; Andrake, M.D.; Katz, R.A. Successes and challenges with retroviral enzymes. Postepy Biochem.,  2016, 62(3), 280-285.
[PMID:  28132482] 
[28] 
Katz, R.A.; Skalka, A.M. The retroviral enzymes. Annu. Rev. Biochem.,  1994, 63, 133-173.
[http://dx.doi.org/10.1146/annurev.bi.63.070194.001025] [PMID:  7526778] 
[29] 
Freed, E.O. HIV-1 gag proteins: diverse functions in the virus life cycle. Virology,  1998, 251(1), 1-15.
[http://dx.doi.org/10.1006/viro.1998.9398] [PMID:  9813197] 
[30] 
Swanstrom, R.; Coffin, J. HIV-1 pathogenesis: The virus. Cold Spring Harb. Perspect. Med.,  2012, 2(12)a007443
[http://dx.doi.org/10.1101/cshperspect.a007443] [PMID:  23143844] 
[31] 
Bond, J.S. Proteases: History, discovery, and roles in health and disease. J. Biol. Chem.,  2019, 294(5), 1643-1651.
[http://dx.doi.org/10.1074/jbc.TM118.004156] [PMID:  30710012] 
[32] 
Tyndall, J.D.A.; Nall, T.; Fairlie, D.P. Proteases universally recognize beta strands in their active sites. Chem. Rev.,  2005, 105(3), 973-999.
[http://dx.doi.org/10.1021/cr040669e] [PMID:  15755082] 
[33] 
Agbowuro, A.A.; Huston, W.M.; Gamble, A.B.; Tyndall, J.D.A. Proteases and protease inhibitors in infectious diseases. Med. Res. Rev.,  2018, 38(4), 1295-1331.
[http://dx.doi.org/10.1002/med.21475] [PMID:  29149530] 
[34] 
Schechter, I.; Berger, A. On the size of the active site in proteases. I. Papain. 1967. Biochem. Biophys. Res. Commun.,  2012, 425(3), 497-502.
[http://dx.doi.org/10.1016/j.bbrc.2012.08.015] [PMID:  22925665] 
[35] 
Schechter, I.; Berger, A. On the size of the active site in proteases. I. Papain. Biochem. Biophys. Res. Commun.,  1967, 27(2), 157-162.
[http://dx.doi.org/10.1016/S0006-291X(67)80055-X] [PMID:  6035483] 
[36] 
Sundquist, W.I.; Kräusslich, H.G. HIV-1 assembly, budding, and maturation. Cold Spring Harb. Perspect. Med.,  2012, 2(7)a006924
[http://dx.doi.org/10.1101/cshperspect.a006924] [PMID:  22762019] 
[37] 
Kohl, N.E.; Emini, E.A.; Schleif, W.A.; Davis, L.J.; Heimbach, J.C.; Dixon, R.A.; Scolnick, E.M.; Sigal, I.S. Active human immunodeficiency virus protease is required for viral infectivity. Proc. Natl. Acad. Sci. USA,  1988, 85(13), 4686-4690.
[http://dx.doi.org/10.1073/pnas.85.13.4686] [PMID:  3290901] 
[38] 
Kramer, R.A.; Schaber, M.D.; Skalka, A.M.; Ganguly, K.; Wong-Staal, F.; Reddy, E.P. HTLV-III gag protein is processed in yeast cells by the virus pol-protease. Science,  1986, 231(4745), 1580-1584.
[http://dx.doi.org/10.1126/science.2420008] [PMID:  2420008] 
[39] 
Debouck, C. The HIV-1 protease as a therapeutic target for AIDS. AIDS Res. Hum. Retroviruses,  1992, 8(2), 153-164.
[http://dx.doi.org/10.1089/aid.1992.8.153] [PMID:  1540403] 
[40] 
Nelson, D.L.; Cox, M.M. Lehninger principles of biochemistry. In: Macmillan Learning, 6th ed; Freeman, W. H. & Company: New York, 2012. 
[41] 
Roberts, N.A.; Martin, J.A.; Kinchington, D.; Broadhurst, A.V.; Craig, J.C.; Duncan, I.B.; Galpin, S.A.; Handa, B.K.; Kay, J.; Kröhn, A. Rational design of peptide-based HIV proteinase inhibitors. Science,  1990, 248(4953), 358-361.
[http://dx.doi.org/10.1126/science.2183354] [PMID:  2183354] 
[42] 
Krohn, A.; Redshaw, S.; Ritchie, J.C.; Graves, B.J.; Hatada, M.H. Novel binding mode of highly potent HIV-proteinase inhibitors incorporating the (R)-hydroxyethylamine isostere. J. Med. Chem.,  1991, 34(11), 3340-3342.
[http://dx.doi.org/10.1021/jm00115a028] [PMID:  1956054] 
[43] 
Ghosh, A.; Anderson, D.D.; Mitsuya, H. The FDA approved HIV-1 protease inhibitors for treatment of HIV/AIDS. In: Burger’s Medicinal Chemistry and Drug Discovery; Abraham, D.J.; Rotella, D.P., Eds.; John Wiley & Sons, Inc.: New Jersey, 2010; Vol. 7, pp. 1-74.
[44] 
Prabu-Jeyabalan, M.; Nalivaika, E.; Schiffer, C.A. Substrate shape determines specificity of recognition for HIV-1 protease: analysis of crystal structures of six substrate complexes. Structure,  2002, 10(3), 369-381.
[http://dx.doi.org/10.1016/S0969-2126(02)00720-7] [PMID:  12005435] 
[45] 
Altman, M.D.; Ali, A.; Reddy, G.S.; Nalam, M.N.; Anjum, S.G.; Cao, H.; Chellappan, S.; Kairys, V.; Fernandes, M.X.; Gilson, M.K.; Schiffer, C.A.; Rana, T.M.; Tidor, B. HIV-1 protease inhibitors from inverse design in the substrate envelope exhibit subnanomolar binding to drug-resistant variants. J. Am. Chem. Soc.,  2008, 130(19), 6099-6113.
[http://dx.doi.org/10.1021/ja076558p] [PMID:  18412349] 
[46] 
Prabu-Jeyabalan, M.; King, N.M.; Nalivaika, E.A.; Heilek-Snyder, G.; Cammack, N.; Schiffer, C.A. Substrate envelope and drug resistance: Crystal structure of RO1 in complex with wild-type human immunodeficiency virus type 1 protease. Antimicrob. Agents Chemother.,  2006, 50(4), 1518-1521.
[http://dx.doi.org/10.1128/AAC.50.4.1518-1521.2006] [PMID:  16569872] 
[47] 
Logsdon, B.C.; Vickrey, J.F.; Martin, P.; Proteasa, G.; Koepke, J.I.; Terlecky, S.R.; Wawrzak, Z.; Winters, M.A.; Merigan, T.C.; Kovari, L.C. Crystal structures of a multidrug-resistant human immunodeficiency virus type 1 protease reveal an expanded active-site cavity. J. Virol.,  2004, 78(6), 3123-3132.
[http://dx.doi.org/10.1128/JVI.78.6.3123-3132.2004] [PMID:  14990731] 
[48] 
Lefebvre, E.; Schiffer, C.A. Resilience to resistance of HIV-1 protease inhibitors: profile of darunavir. AIDS Rev.,  2008, 10(3), 131-142.
[PMID:  18820715] 
[49] 
Shen, Y.; Altman, M.D.; Ali, A.; Nalam, M.N.; Cao, H.; Rana, T.M.; Schiffer, C.A.; Tidor, B. Testing the substrate-envelope hypothesis with designed pairs of compounds. ACS Chem. Biol.,  2013, 8(11), 2433-2441.
[http://dx.doi.org/10.1021/cb400468c] [PMID:  23952265] 
[50] 
Nalam, M.N.; Ali, A.; Reddy, G.S.; Cao, H.; Anjum, S.G.; Altman, M.D.; Yilmaz, N.K.; Tidor, B.; Rana, T.M.; Schiffer, C.A. Substrate envelope-designed potent HIV-1 protease inhibitors to avoid drug resistance. Chem. Biol.,  2013, 20(9), 1116-1124.
[http://dx.doi.org/10.1016/j.chembiol.2013.07.014] [PMID:  24012370] 
[51] 
Mimoto, T.; Imai, J.; Tanaka, S.; Hattori, N.; Takahashi, O.; Kisanuki, S.; Nagano, Y.; Shintani, M.; Hayashi, H.; Sakikawa, H. Rational design and synthesis of a novel class of active site-targeted HIV protease inhibitors containing a hydroxymethylcarbonyl isostere. Use of phenylnorstatine or allophenylnorstatine as a transition-state mimic. Chem. Pharm. Bull. (Tokyo),  1991, 39(9), 2465-2467.
[http://dx.doi.org/10.1248/cpb.39.2465] [PMID:  1804562] 
[52] 
Raju, B.; Deshpande, M.S. Investigating the stereochemistry of binding to HIV-1 protease with inhibitors containing isomers of 4-amino-3-hydroxy-5-phenylpentanoic acid. Biochem. Biophys. Res. Commun.,  1991, 180(1), 187-190.
[http://dx.doi.org/10.1016/S0006-291X(05)81274-4] [PMID:  1930215] 
[53] 
Fehrentz, J.A.; Chomier, B.; Bignon, E.; Venaud, S.; Chermann, J.C.; Nisato, D. Statine based tripeptides as potent inhibitors of HIV-1 replication. Biochem. Biophys. Res. Commun.,  1992, 188(2), 873-878.
[http://dx.doi.org/10.1016/0006-291X(92)91137-F] [PMID:  1445328] 
[54] 
Sakurai, M.; Sugano, M.; Handa, H.; Komai, T.; Yagi, R.; Nishigaki, T.; Yabe, Y. Studies of HIV-1 protease inhibitors. I. Incorporation of a reduced peptide, simple aminoalcohol, and statine analog at the scissile site of substrate sequences. Chem. Pharm. Bull. (Tokyo),  1993, 41(8), 1369-1377.
[http://dx.doi.org/10.1248/cpb.41.1369] [PMID:  8403085] 
[55] 
Tam, T.F.; Carrière, J.; MacDonald, D.; Castelhano, A.L.; Pliura, D.H.; Dewdney, N.J.; Thomas, E.M.; Bach, C.; Barnett, J.; Chan, H. Intriguing structure-activity relations underlie the potent inhibition of HIV protease by norstatine-based peptides. J. Med. Chem.,  1992, 35(7), 1318-1320.
[http://dx.doi.org/10.1021/jm00085a020] [PMID:  1560443] 
[56] 
H., Slee D.; L.Laslo, K.; H. Elder, J.; R.Ollmann, I.; Gustchina, A.; Kervinen, J.; Zdanov, A.; Wlodawer, A.; Wong, C.-H. Selectivity in the inhibition of HIV and FIV protease: Inhibitory and mechanistic studies of pyrrolidine-containing. alpha.-keto amide and hydroxyethylamine core structures. J. Am. Chem. Soc.,  1995, 117(48), 11867-11878.
[http://dx.doi.org/10.1021/ja00153a008] 
[57] 
Tie, Y.; Boross, P.I.; Wang, Y.F.; Gaddis, L.; Hussain, A.K.; Leshchenko, S.; Ghosh, A.K.; Louis, J.M.; Harrison, R.W.; Weber, I.T. High resolution crystal structures of HIV-1 protease with a potent non-peptide inhibitor (UIC-94017) active against multi-drug-resistant clinical strains. J. Mol. Biol.,  2004, 338(2), 341-352.
[http://dx.doi.org/10.1016/j.jmb.2004.02.052] [PMID:  15066436] 
[58] 
Ghosh, A.K.; Martyr, C.D.; Steffey, M.; Wang, Y.F.; Agniswamy, J.; Amano, M.; Weber, I.T.; Mitsuya, H. Design of substituted bis-Tetrahydrofuran (bis-THF)-derived potent HIV-1 protease inhibitors, protein-ligand X-ray structure, and convenient syntheses of bis-THF and substituted bis-THF ligands. ACS Med. Chem. Lett.,  2011, 2(4), 298-302.
[http://dx.doi.org/10.1021/ml100289m] [PMID:  22509432] 
[59] 
Ghosh, A.K.; Chapsal, B.D.; Baldridge, A.; Steffey, M.P.; Walters, D.E.; Koh, Y.; Amano, M.; Mitsuya, H. Design and synthesis of potent HIV-1 protease inhibitors incorporating hexahydrofuropyranol-derived high affinity P(2) ligands: structure-activity studies and biological evaluation. J. Med. Chem.,  2011, 54(2), 622-634.
[http://dx.doi.org/10.1021/jm1012787] [PMID:  21194227] 
[60] 
Ghosh, A.K.; Chapsal, B.D.; Parham, G.L.; Steffey, M.; Agniswamy, J.; Wang, Y.F.; Amano, M.; Weber, I.T.; Mitsuya, H. Design of HIV-1 protease inhibitors with C3-substituted hexahydrocyclopentafuranyl urethanes as P2-ligands: synthesis, biological evaluation, and protein-ligand X-ray crystal structure. J. Med. Chem.,  2011, 54(16), 5890-5901.
[http://dx.doi.org/10.1021/jm200649p] [PMID:  21800876] 
[61] 
Ghosh, A.K.; Chapsal, B.D.; Steffey, M.; Agniswamy, J.; Wang, Y.F.; Amano, M.; Weber, I.T.; Mitsuya, H. Substituent effects on P2-cyclopentyltetrahydrofuranyl urethanes: design, synthesis, and X-ray studies of potent HIV-1 protease inhibitors. Bioorg. Med. Chem. Lett.,  2012, 22(6), 2308-2311.
[http://dx.doi.org/10.1016/j.bmcl.2012.01.061] [PMID:  22364812] 
[62] 
Ghosh, A.K.; Leshchenko-Yashchuk, S.; Anderson, D.D.; Baldridge, A.; Noetzel, M.; Miller, H.B.; Tie, Y.; Wang, Y.F.; Koh, Y.; Weber, I.T.; Mitsuya, H. Design of HIV-1 protease inhibitors with pyrrolidinones and oxazolidinones as novel P1′-ligands to enhance backbone-binding interactions with protease: synthesis, biological evaluation, and protein-ligand X-ray studies. J. Med. Chem.,  2009, 52(13), 3902-3914.
[http://dx.doi.org/10.1021/jm900303m] [PMID:  19473017] 
[63] 
Hornak, V.; Okur, A.; Rizzo, R.C.; Simmerling, C. HIV-1 protease flaps spontaneously close to the correct structure in simulations following manual placement of an inhibitor into the open state. J. Am. Chem. Soc.,  2006, 128(9), 2812-2813.
[http://dx.doi.org/10.1021/ja058211x] [PMID:  16506755] 
[64] 
Layten, M.; Hornak, V.; Simmerling, C. The open structure of a multi-drug-resistant HIV-1 protease is stabilized by crystal packing contacts. J. Am. Chem. Soc.,  2006, 128(41), 13360-13361.
[http://dx.doi.org/10.1021/ja065133k] [PMID:  17031940] 
[65] 
Hornak, V.; Simmerling, C. Targeting structural flexibility in HIV-1 protease inhibitor binding. Drug Discov. Today,  2007, 12(3-4), 132-138.
[http://dx.doi.org/10.1016/j.drudis.2006.12.011] [PMID:  17275733] 
[66] 
Ishima, R.; Freedberg, D.I.; Wang, Y-X.; Louis, J.M.; Torchia, D.A. Flap opening and dimer-interface flexibility in the free and inhibitor-bound HIV protease, and their implications for function. Structure,  1999, 7(9), 1047-1055.
[http://dx.doi.org/10.1016/S0969-2126(99)80172-5] [PMID:  10508781] 
[67] 
Hornak, V.; Okur, A.; Rizzo, R.C.; Simmerling, C. HIV-1 protease flaps spontaneously open and reclose in molecular dynamics simulations. Proc. Natl. Acad. Sci. USA,  2006, 103(4), 915-920.
[http://dx.doi.org/10.1073/pnas.0508452103] [PMID:  16418268] 
[68] 
Specker, E.; Böttcher, J.; Brass, S.; Heine, A.; Lilie, H.; Schoop, A.; Müller, G.; Griebenow, N.; Klebe, G. Unexpected novel binding mode of pyrrolidine-based aspartyl protease inhibitors: design, synthesis and crystal structure in complex with HIV protease. ChemMedChem,  2006, 1(1), 106-117.
[http://dx.doi.org/10.1002/cmdc.200500008] [PMID:  16892342] 
[69] 
Böttcher, J.; Blum, A.; Dörr, S.; Heine, A.; Diederich, W.E.; Klebe, G. Targeting the open-flap conformation of HIV-1 protease with pyrrolidine-based inhibitors. ChemMedChem,  2008, 3(9), 1337-1344.
[http://dx.doi.org/10.1002/cmdc.200800113] [PMID:  18720485] 
[70] 
Cígler, P.; Kozísek, M.; Rezácová, P.; Brynda, J.; Otwinowski, Z.; Pokorná, J.; Plesek, J.; Grüner, B.; Dolecková-Maresová, L.; Mása, M.; Sedlácek, J.; Bodem, J.; Kräusslich, H.G.; Král, V.; Konvalinka, J. From nonpeptide toward noncarbon protease inhibitors: metallacarboranes as specific and potent inhibitors of HIV protease. Proc. Natl. Acad. Sci. USA,  2005, 102(43), 15394-15399.
[http://dx.doi.org/10.1073/pnas.0507577102] [PMID:  16227435] 
[71] 
Lam, P.Y.; Jadhav, P.K.; Eyermann, C.J.; Hodge, C.N.; Ru, Y.; Bacheler, L.T.; Meek, J.L.; Otto, M.J.; Rayner, M.M.; Wong, Y.N. Rational design of potent, bioavailable, nonpeptide cyclic ureas as HIV protease inhibitors. Science,  1994, 263(5145), 380-384.
[http://dx.doi.org/10.1126/science.8278812] [PMID:  8278812] 
[72] 
Ala, P.J.; DeLoskey, R.J.; Huston, E.E.; Jadhav, P.K.; Lam, P.Y.; Eyermann, C.J.; Hodge, C.N.; Schadt, M.C.; Lewandowski, F.A.; Weber, P.C.; McCabe, D.D.; Duke, J.L.; Chang, C.H. Molecular recognition of cyclic urea HIV-1 protease inhibitors. J. Biol. Chem.,  1998, 273(20), 12325-12331.
[http://dx.doi.org/10.1074/jbc.273.20.12325] [PMID:  9575185] 
[73] 
Pierce, M.E.; Harris, G.D.; Islam, Q.; Radesca, L.A.; Storace, L.; Waltermire, R.E.; Wat, E.; Jadhav, P.K.; Emmett, G.C. Stereoselective synthesis of HIV-1 protease inhibitor, DMP 323. J. Org. Chem.,  1996, 61(2), 444-450.
[http://dx.doi.org/10.1021/jo951847u] [PMID:  11666958] 
[74] 
Pokorná, J.; Machala, L.; Rezáčová, P.; Konvalinka, J. Current and novel inhibitors of HIV protease. Viruses,  2009, 1(3), 1209-1239.
[http://dx.doi.org/10.3390/v1031209] [PMID:  21994591] 
[75] 
Ghosh, A.K.; Osswald, H.L.; Prato, G. Recent progress in the development of HIV-1 protease inhibitors for the treatment of HIV/AIDS. J. Med. Chem.,  2016, 59(11), 5172-5208.
[http://dx.doi.org/10.1021/acs.jmedchem.5b01697] [PMID:  26799988] 
[76] 
Lam, P.Y.; Ru, Y.; Jadhav, P.K.; Aldrich, P.E.; DeLucca, G.V.; Eyermann, C.J.; Chang, C.H.; Emmett, G.; Holler, E.R.; Daneker, W.F.; Li, L.; Confalone, P.N.; McHugh, R.J.; Han, Q.; Li, R.; Markwalder, J.A.; Seitz, S.P.; Sharpe, T.R.; Bacheler, L.T.; Rayner, M.M.; Klabe, R.M.; Shum, L.; Winslow, D.L.; Kornhauser, D.M.; Hodge, C.N. Cyclic HIV protease inhibitors: Synthesis, conformational analysis, P2/P2′ structure-activity relationship, and molecular recognition of cyclic ureas. J. Med. Chem.,  1996, 39(18), 3514-3525.
[http://dx.doi.org/10.1021/jm9602571] [PMID:  8784449] 
[77] 
Patel, M.; Bacheler, L.T.; Rayner, M.M.; Cordova, B.C.; Klabe, R.M.; Erickson-Viitanen, S.; Seitz, S.P. The synthesis and evaluation of cyclic ureas as HIV protease inhibitors: modifications of the P1/P1′ residues. Bioorg. Med. Chem. Lett.,  1998, 8(7), 823-828.
[http://dx.doi.org/10.1016/S0960-894X(98)00119-X] [PMID:  9871548] 
[78] 
Mimoto, T.; Hattori, N.; Takaku, H.; Kisanuki, S.; Fukazawa, T.; Terashima, K.; Kato, R.; Nojima, S.; Misawa, S.; Ueno, T.; Imai, J.; Enomoto, H.; Tanaka, S.; Sakikawa, H.; Shintani, M.; Hayashi, H.; Kiso, Y. Structure-activity relationship of orally potent tripeptide-based HIV protease inhibitors containing hydroxymethylcarbonyl isostere. Chem. Pharm. Bull. (Tokyo),  2000, 48(9), 1310-1326.
[http://dx.doi.org/10.1248/cpb.48.1310] [PMID:  10993230] 
[79] 
Kageyama, S.; Hoekzema, D.T.; Murakawa, Y.; Kojima, E.; Shirasaka, T.; Kempf, D.J.; Norbeck, D.W.; Erickson, J.; Mitsuya, H.A. C2 symmetry-based HIV protease inhibitor, A77003, irreversibly inhibits infectivity of HIV-1 in vitro. AIDS Res. Hum. Retroviruses,  1994, 10(6), 735-743.
[http://dx.doi.org/10.1089/aid.1994.10.735] [PMID:  8074936] 
[80] 
Appelt, K. Crystal structures of HIV-1 protease-inhibitor complexes. Perspect. Drug Discov. Des.,  1993, 1(1), 23-48.
[http://dx.doi.org/10.1007/BF02171654] 
[81] 
Babine, R.E.; Bender, S.L. Molecular recognition of proteinminus signligand complexes: Applications to drug design. Chem. Rev.,  1997, 97(5), 1359-1472.
[http://dx.doi.org/10.1021/cr960370z] [PMID:  11851455] 
[82] 
Dreyer, G.B.; Metcalf, B.W.; Tomaszek, T.A., Jr; Carr, T.J.; Chandler, A.C., III; Hyland, L.; Fakhoury, S.A.; Magaard, V.W.; Moore, M.L.; Strickler, J.E. Inhibition of human immunodeficiency virus 1 protease in vitro: rational design of substrate analogue inhibitors. Proc. Natl. Acad. Sci. USA,  1989, 86(24), 9752-9756.
[http://dx.doi.org/10.1073/pnas.86.24.9752] [PMID:  2690072] 
[83] 
Meek, T.D.; Lambert, D.M.; Dreyer, G.B.; Carr, T.J.; Tomaszek, T.A., Jr; Moore, M.L.; Strickler, J.E.; Debouck, C.; Hyland, L.J.; Matthews, T.J. Inhibition of HIV-1 protease in infected T-lymphocytes by synthetic peptide analogues. Nature,  1990, 343(6253), 90-92.
[http://dx.doi.org/10.1038/343090a0] [PMID:  1688646] 
[84] 
Dreyer, G.B.; Lambert, D.M.; Meek, T.D.; Carr, T.J.; Tomaszek, T.A., Jr; Fernandez, A.V.; Bartus, H.; Cacciavillani, E.; Hassell, A.M.; Minnich, M. Hydroxyethylene isostere inhibitors of human immunodeficiency virus-1 protease: structure-activity analysis using enzyme kinetics, X-ray crystallography, and infected T-cell assays. Biochemistry,  1992, 31(29), 6646-6659.
[http://dx.doi.org/10.1021/bi00144a004] [PMID:  1637805] 
[85] 
Kim, E.E.; Baker, C.T.; Dwyer, M.D.; Murcko, M.A.; Rao, B.G.; Tung, R.D.; Navia, M.A. Crystal structure of HIV-1 protease in complex with VX-478, a potent and orally bioavailable inhibitor of the enzyme. J. Am. Chem. Soc.,  1995, 117(3), 1181-1182.
[http://dx.doi.org/10.1021/ja00108a056] 
[86] 
Kaldor, S.W.; Hammond, M.; Dressman, B.A.; Fritz, J.E.; Crowell, T.A.; Hermann, R.A. New dipeptide isosteres useful for the inhibition of HIV-1 protease. Bioorg. Med. Chem. Lett.,  1994, 4(11), 1385-1390.
[http://dx.doi.org/10.1016/S0960-894X(01)80367-X] 
[87] 
Stoner, E.J.; Cooper, A.J.; Dickman, D.A.; Kolaczkowski, L.; Lallaman, J.E.; Liu, J-H.; Oliver-Shaffer, P.A.; Patel, K.M.; Paterson, J.B.; Plata, D.J.; Riley, D.A.; Sham, H.L.; Stengel, P.J.; Tien, J-H.J. Synthesis of HIV protease inhibitor ABT-378 (lopinavir). Org. Process Res. Dev.,  2000, 4(4), 264-269.
[http://dx.doi.org/10.1021/op990202j] 
[88] 
Kempf, D.J.; Sham, H.L.; Marsh, K.C.; Flentge, C.A.; Betebenner, D.; Green, B.E.; McDonald, E.; Vasavanonda, S.; Saldivar, A.; Wideburg, N.E.; Kati, W.M.; Ruiz, L.; Zhao, C.; Fino, L.; Patterson, J.; Molla, A.; Plattner, J.J.; Norbeck, D.W. Discovery of ritonavir, a potent inhibitor of HIV protease with high oral bioavailability and clinical efficacy. J. Med. Chem.,  1998, 41(4), 602-617.
[http://dx.doi.org/10.1021/jm970636+] [PMID:  9484509] 
[89] 
Munoz, B.; Giam, C.Z.; Wong, C.H. Alpha-ketoamide Phe-Pro isostere as a new core structure for the inhibition of HIV protease. Bioorg. Med. Chem.,  1994, 2(10), 1085-1090.
[http://dx.doi.org/10.1016/S0968-0896(00)82058-1] [PMID:  7773625] 
[90] 
Wolfenden, R. Conformational aspects of inhibitor design: Enzyme-substrate interactions in the transition state. Bioorg. Med. Chem.,  1999, 7(5), 647-652.
[http://dx.doi.org/10.1016/S0968-0896(98)00247-8] [PMID:  10400319] 
[91] 
Sakurai, M.; Sugano, M.; Handa, H.; Komai, T.; Yagi, R.; Nishigaki, T.; Yabe, Y. Studies of HIV-1 protease inhibitors. I. Incorporation of a reduced peptide, simple aminoalcohol, and statine analog at the scissile site of substrate sequences. Chem. Pharm. Bull. (Tokyo),  1993, 41(8), 1369-1377.
[http://dx.doi.org/10.1248/cpb.41.1369] [PMID:  8403085] 
[92] 
Slee, D.H.; Laslo, K.L.; Elder, J.H.; Ollmann, I.R.; Gustchina, A.; Kervinen, J.; Zdanov, A.; Wlodawer, A.; Wong, C-H. Selectivity in the inhibition of HIV and FIV protease: Inhibitory and mechanistic studies of pyrrolidine-containing. alpha.-keto amide and hydroxyethylamine Core Structures. J. Am. Chem. Soc.,  1995, 117(48), 11867-11878.
[http://dx.doi.org/10.1021/ja00153a008] 
[93] 
Piliero, P.J. Atazanavir: A novel HIV-1 protease inhibitor. Expert Opin. Investig. Drugs,  2002, 11(9), 1295-1301.
[http://dx.doi.org/10.1517/13543784.11.9.1295] [PMID:  12225250] 
[94] 
Goldsmith, D.R.; Perry, C.M. Atazanavir. Drugs,  2003, 63(16), 1679-1693.
[http://dx.doi.org/10.2165/00003495-200363160-00003] [PMID:  12904086] 
[95] 
Skulnick, H.I.; Johnson, P.D.; Aristoff, P.A.; Morris, J.K.; Lovasz, K.D.; Howe, W.J.; Watenpaugh, K.D.; Janakiraman, M.N.; Anderson, D.J.; Reischer, R.J.; Schwartz, T.M.; Banitt, L.S.; Tomich, P.K.; Lynn, J.C.; Horng, M-M.; Chong, K-T.; Hinshaw, R.R.; Dolak, L.A.; Seest, E.P.; Schwende, F.J.; Rush, B.D.; Howard, G.M.; Toth, L.N.; Wilkinson, K.R.; Romines, K.R.; Johnson, C.W.; Cole, S.L.; Zaya, R.M.; Zipp, G.L.; Possert, P.L.; Dalga, R.J.; Zhong, W-Z.; Williams, M.G.; Romines, K.R. Structure-based design of nonpeptidic HIV protease inhibitors: the sulfonamide-substituted cyclooctylpyramones. J. Med. Chem.,  1997, 40(7), 1149-1164.
[http://dx.doi.org/10.1021/jm960441m] [PMID:  9089336] 
[96] 
Hayashi, H.; Takamune, N.; Nirasawa, T.; Aoki, M.; Morishita, Y.; Das, D.; Koh, Y.; Ghosh, A.K.; Misumi, S.; Mitsuya, H. Dimerization of HIV-1 protease occurs through two steps relating to the mechanism of protease dimerization inhibition by darunavir. Proc. Natl. Acad. Sci. USA,  2014, 111(33), 12234-12239.
[http://dx.doi.org/10.1073/pnas.1400027111] [PMID:  25092296] 
[97] 
Todd, M.J.; Semo, N.; Freire, E. The structural stability of the HIV-1 protease. J. Mol. Biol.,  1998, 283(2), 475-488.
[http://dx.doi.org/10.1006/jmbi.1998.2090] [PMID:  9769219] 
[98] 
Davis, D.A.; Brown, C.A.; Singer, K.E.; Wang, V.; Kaufman, J.; Stahl, S.J.; Wingfield, P.; Maeda, K.; Harada, S.; Yoshimura, K.; Kosalaraksa, P.; Mitsuya, H.; Yarchoan, R. Inhibition of HIV-1 replication by a peptide dimerization inhibitor of HIV-1 protease. Antiviral Res.,  2006, 72(2), 89-99.
[http://dx.doi.org/10.1016/j.antiviral.2006.03.015] [PMID:  16687179] 
[99] 
Koh, Y.; Matsumi, S.; Das, D.; Amano, M.; Davis, D.A.; Li, J.; Leschenko, S.; Baldridge, A.; Shioda, T.; Yarchoan, R.; Ghosh, A.K.; Mitsuya, H. Potent inhibition of HIV-1 replication by novel non-peptidyl small molecule inhibitors of protease dimerization. J. Biol. Chem.,  2007, 282(39), 28709-28720.
[http://dx.doi.org/10.1074/jbc.M703938200] [PMID:  17635930] 
[100] 
Koh, Y.; Aoki, M.; Danish, M.L.; Aoki-Ogata, H.; Amano, M.; Das, D.; Shafer, R.W.; Ghosh, A.K.; Mitsuya, H. Loss of protease dimerization inhibition activity of darunavir is associated with the acquisition of resistance to darunavir by HIV-1. J. Virol.,  2011, 85(19), 10079-10089.
[http://dx.doi.org/10.1128/JVI.05121-11] [PMID:  21813613] 
[101] 
Bannwarth, L.; Kessler, A.; Pèthe, S.; Collinet, B.; Merabet, N.; Boggetto, N.; Sicsic, S.; Reboud-Ravaux, M.; Ongeri, S. Molecular tongs containing amino acid mimetic fragments: new inhibitors of wild-type and mutated HIV-1 protease dimerization. J. Med. Chem.,  2006, 49(15), 4657-4664.
[http://dx.doi.org/10.1021/jm060576k] [PMID:  16854071] 
[102] 
Vidu, A.; Dufau, L.; Bannwarth, L.; Soulier, J.L.; Sicsic, S.; Piarulli, U.; Reboud-Ravaux, M.; Ongeri, S. Toward the first nonpeptidic molecular tong inhibitor of wild-type and mutated HIV-1 protease dimerization. ChemMedChem,  2010, 5(11), 1899-1906.
[http://dx.doi.org/10.1002/cmdc.201000308] [PMID:  20936621] 
[103] 
Dufau, L.; Marques Ressurreição, A.S.; Fanelli, R.; Kihal, N.; Vidu, A.; Milcent, T.; Soulier, J.L.; Rodrigo, J.; Desvergne, A.; Leblanc, K.; Bernadat, G.; Crousse, B.; Reboud-Ravaux, M.; Ongeri, S. Carbonylhydrazide-based molecular tongs inhibit wild-type and mutated HIV-1 protease dimerization. J. Med. Chem.,  2012, 55(15), 6762-6775.
[http://dx.doi.org/10.1021/jm300181j] [PMID:  22800535] 
[104] 
Lee, S.G.; Chmielewski, J. Cross-linked peptoid-based dimerization inhibitors of HIV-1 protease. ChemBioChem,  2010, 11(11), 1513-1516.
[http://dx.doi.org/10.1002/cbic.201000248] [PMID:  20575134] 
[105] 
Bowman, M.J.; Byrne, S.; Chmielewski, J. Switching between allosteric and dimerization inhibition of HIV-1 protease. Chem. Biol.,  2005, 12(4), 439-444.
[http://dx.doi.org/10.1016/j.chembiol.2005.02.004] [PMID:  15850980] 
[106] 
Kempf, D.J.; Norbeck, D.W.; Codacovi, L.; Wang, X.C.; Kohlbrenner, W.E.; Wideburg, N.E.; Paul, D.A.; Knigge, M.F.; Vasavanonda, S.; Craig-Kennard, A. Structure-based, C2 symmetric inhibitors of HIV protease. J. Med. Chem.,  1990, 33(10), 2687-2689.
[http://dx.doi.org/10.1021/jm00172a002] [PMID:  2213822] 
[107] 
Kempf, D.J.; Codacovi, L.; Wang, X.C.; Kohlbrenner, W.E.; Wideburg, N.E.; Saldivar, A.; Vasavanonda, S.; Marsh, K.C.; Bryant, P.; Sham, H.L. Symmetry-based inhibitors of HIV protease. Structure-activity studies of acylated 2,4-diamino-1,5-diphenyl-3-hydroxypentane and 2,5-diamino-1,6-diphenylhexane-3,4-diol. J. Med. Chem.,  1993, 36(3), 320-330.
[PMID:  8426362] 
[108] 
Erickson, J.; Neidhart, D.J.; VanDrie, J.; Kempf, D.J.; Wang, X.C.; Norbeck, D.W.; Plattner, J.J.; Rittenhouse, J.W.; Turon, M.; Wideburg, N. Design, activity, and 2.8 A crystal structure of a C2 symmetric inhibitor complexed to HIV-1 protease. Science,  1990, 249(4968), 527-533.
[http://dx.doi.org/10.1126/science.2200122] [PMID:  2200122] 
[109] 
Reedijk, M.; Boucher, C.A.; van Bommel, T.; Ho, D.D.; Tzeng, T.B.; Sereni, D.; Veyssier, P.; Jurriaans, S.; Granneman, R.; Hsu, A. Safety, pharmacokinetics, and antiviral activity of A77003, a C2 symmetry-based human immunodeficiency virus protease inhibitor. Antimicrob. Agents Chemother.,  1995, 39(7), 1559-1564.
[http://dx.doi.org/10.1128/AAC.39.7.1559] [PMID:  7492104] 
[110] 
Kempf, D.J.; Marsh, K.C.; Denissen, J.F.; McDonald, E.; Vasavanonda, S.; Flentge, C.A.; Green, B.E.; Fino, L.; Park, C.H.; Kong, X.P. ABT-538 is a potent inhibitor of human immunodeficiency virus protease and has high oral bioavailability in humans. Proc. Natl. Acad. Sci. USA,  1995, 92(7), 2484-2488.
[http://dx.doi.org/10.1073/pnas.92.7.2484] [PMID:  7708670] 
[111] 
Budt, K.H.; Peyman, A.; Hansen, J.; Knolle, J.; Meichsner, C.; Paessens, A.; Ruppert, D.; Stowasser, B. HIV protease inhibitor HOE/BAY 793, structure-activity relationships in a series of C2-symmetric diols. Bioorg. Med. Chem.,  1995, 3(5), 559-571.
[http://dx.doi.org/10.1016/0968-0896(95)00069-S] [PMID:  7648204] 
[112] 
Ettmayer, P.; Hübner, M.; Andreas, B.; Brigitte, R.; Hubert, G. Novel, extended transition state mimic in HIV-1 protease inhibitors with peripheral C-2-symmetry. Bioorg. Med. Chem. Lett.,  1994, 4(24), 2851-2856.
[http://dx.doi.org/10.1016/S0960-894X(01)80827-1] 
[113] 
Mo, H.; Markowitz, M.; Majer, P.; Burt, S.K.; Gulnik, S.V.; Suvorov, L.I.; Erickson, J.W.; Ho, D.D. Design, synthesis, and resistance patterns of MP-134 and MP-167, two novel inhibitors of HIV type 1 protease. AIDS Res. Hum. Retroviruses,  1996, 12(1), 55-61.
[http://dx.doi.org/10.1089/aid.1996.12.55] [PMID:  8825619] 
[114] 
Kempf, D.J. Design of symmetry-based, peptidomimetic inhibitors of human immunodeficiency virus protease. Methods Enzymol.,  1994, 241, 334-354.
[http://dx.doi.org/10.1016/0076-6879(94)41072-0] [PMID:  7854187] 
[115] 
Bone, R.; Vacca, J.P.; Anderson, P.S.; Holloway, M.K. X-ray crystal structure of the HIV protease complex with L-700,417, an inhibitor with pseudo C2 symmetry. J. Am. Chem. Soc.,  1991, 113(24), 9382-9384.
[http://dx.doi.org/10.1021/ja00024a061] 
[116] 
Babine, R.E.; Zhang, N.; Schow, S.R.; Jirousek, M.R.; Johnson, B.D.; Kerwar, S.S.; Desai, P.R.; Byrn, R.A.; Hastings, R.C.; Wick, M.M. Structure activity studies on pseudo-symmetrical HIV-1 protease inhibitors. Bioorg. Med. Chem. Lett.,  1993, 3(8), 1589-1594.
[http://dx.doi.org/10.1016/S0960-894X(00)80023-2] 
[117] 
Marastoni, M.; Bergonzoni, M.; Bortolotti, F.; Tomatis, R. Symmetry-based HIV protease inhibitors containing (S,S) or (R,R) tartaric acid core structure. Arzneimittelforschung,  1997, 47(7), 889-892.
[PMID:  9272250] 
[118] 
Peçanha, E.P.; Figueiredo, L.J.; Brindeiro, R.M.; Tanuri, A.; Calazans, A.R.; Antunes, O.A. Synthesis and anti-HIV activity of new C2 symmetric derivatives designed as HIV-1 protease inhibitors. Farmaco,  2003, 58(2), 149-157.
[http://dx.doi.org/10.1016/S0014-827X(02)00016-2] [PMID:  12581781] 
[119] 
da Cunha, E.F.; Sippl, W.; de Castro Ramalho, T.; Ceva Antunes, O.A.; de Alencastro, R.B.; Albuquerque, M.G. 3D-QSAR CoMFA/CoMSIA models based on theoretical active conformers of HOE/BAY-793 analogs derived from HIV-1 protease inhibitor complexes. Eur. J. Med. Chem.,  2009, 44(11), 4344-4352.
[http://dx.doi.org/10.1016/j.ejmech.2009.05.016] [PMID:  19616874] 
[120] 
Arefalk, A.; Wannberg, J.; Larhed, M.; Hallberg, A. Stereoselective synthesis of 3-aminoindan-1-ones and subsequent incorporation into HIV-1 protease inhibitors. J. Org. Chem.,  2006, 71(3), 1265-1268.
[http://dx.doi.org/10.1021/jo0521504] [PMID:  16438552] 
[121] 
Adrian Meredith, J.; Wallberg, H.; Vrang, L.; Oscarson, S.; Parkes, K.; Hallberg, A.; Samuelsson, B. Design and synthesis of novel P2 substituents in diol-based HIV protease inhibitors. Eur. J. Med. Chem.,  2010, 45(1), 160-170.
[http://dx.doi.org/10.1016/j.ejmech.2009.09.038] [PMID:  19926360] 
[122] 
U.S. department of health and human services, National institutes
of health, AIDS info 2019.Saquinavir. (Accessed on March 4,
2019 at. https://aidsinfo.nih.gov/drugs/164/saquinavir/35/professional
[123] 
James, J.S. Saquinavir (Invirase): First protease inhibitor approved--reimbursement, information hotline numbers. AIDS Treat. News,  1995, (237), 1-2.
[PMID:  11363073] 
[124] 
US Food and Drug Administration 2003.Roche, Fortovase®
(saquinavir). (Accessed on March 4, 2019 at. https://www.accessdata.fda.gov/drugsatfda_docs/label/2003/20828s015ppi.pdf
[125] 
Weller, I.V.; Williams, I.G. ABC of AIDS. Antiretroviral drugs. BMJ,  2001, 322(7299), 1410-1412.
[http://dx.doi.org/10.1136/bmj.322.7299.1410] [PMID:  11397751] 
[126] 
Cameron, D.W.; Japour, A.J.; Xu, Y.; Hsu, A.; Mellors, J.; Farthing, C.; Cohen, C.; Poretz, D.; Markowitz, M.; Follansbee, S.; Angel, J.B.; McMahon, D.; Ho, D.; Devanarayan, V.; Rode, R.; Salgo, M.; Kempf, D.J.; Granneman, R.; Leonard, J.M.; Sun, E. Ritonavir and saquinavir combination therapy for the treatment of HIV infection. AIDS,  1999, 13(2), 213-224.
[http://dx.doi.org/10.1097/00002030-199902040-00009] [PMID:  10202827] 
[127] 
Kilby, J.M.; Sfakianos, G.; Gizzi, N.; Siemon-Hryczyk, P.; Ehrensing, E.; Oo, C.; Buss, N.; Saag, M.S. Safety and pharmacokinetics of once-daily regimens of soft-gel capsule saquinavir plus minidose ritonavir in human immunodeficiency virus-negative adults. Antimicrob. Agents Chemother.,  2000, 44(10), 2672-2678.
[http://dx.doi.org/10.1128/AAC.44.10.2672-2678.2000] [PMID:  10991842] 
[128] 
Ananworanich, J.; Gayet-Ageron, A.; Ruxrungtham, K.; Chetchotisakd, P.; Prasithsirikul, W.; Kiertiburanakul, S.; Munsakul, W.; Raksakulkarn, P.; Tansuphasawadikul, S.; LeBraz, M.; Jupimai, T.; Ubolyam, S.; Schutz, M.; Hirschel, B. Long-term efficacy and safety of first-line therapy with once-daily saquinavir/ritonavir. Antivir. Ther. (Lond.),  2008, 13(3), 375-380.
[PMID:  18572750] 
[129] 
Kempf, D.J.; Marsh, K.C.; Fino, L.C.; Bryant, P.; Craig-Kennard, A.; Sham, H.L.; Zhao, C.; Vasavanonda, S.; Kohlbrenner, W.E.; Wideburg, N.E. Design of orally bioavailable, symmetry-based inhibitors of HIV protease. Bioorg. Med. Chem.,  1994, 2(9), 847-858.
[http://dx.doi.org/10.1016/S0968-0896(00)82036-2] [PMID:  7712122] 
[130] 
Kempf, D.J.; Marsh, K.C.; Kumar, G.; Rodrigues, A.D.; Denissen, J.F.; McDonald, E.; Kukulka, M.J.; Hsu, A.; Granneman, G.R.; Baroldi, P.A.; Sun, E.; Pizzuti, D.; Plattner, J.J.; Norbeck, D.W.; Leonard, J.M. Pharmacokinetic enhancement of inhibitors of the human immunodeficiency virus protease by coadministration with ritonavir. Antimicrob. Agents Chemother.,  1997, 41(3), 654-660.
[http://dx.doi.org/10.1128/AAC.41.3.654] [PMID:  9056009] 
[131] 
Moyle, G.J.; Back, D. Principles and practice of HIV-protease inhibitor pharmacoenhancement. HIV Med.,  2001, 2(2), 105-113.
[http://dx.doi.org/10.1046/j.1468-1293.2001.00063.x] [PMID:  11737387] 
[132] 
Zeldin, R.K.; Petruschke, R.A. Pharmacological and therapeutic properties of ritonavir-boosted protease inhibitor therapy in HIV-infected patients. J. Antimicrob. Chemother.,  2004, 53(1), 4-9.
[http://dx.doi.org/10.1093/jac/dkh029] [PMID:  14657084] 
[133] 
Louis, J.M.; Aniana, A.; Weber, I.T.; Sayer, J.M. Inhibition of autoprocessing of natural variants and multidrug resistant mutant precursors of HIV-1 protease by clinical inhibitors. Proc. Natl. Acad. Sci. USA,  2011, 108(22), 9072-9077.
[http://dx.doi.org/10.1073/pnas.1102278108] [PMID:  21576495] 
[134] 
Dorsey, B.D.; Levin, R.B.; McDaniel, S.L.; Vacca, J.P.; Guare, J.P.; Darke, P.L.; Zugay, J.A.; Emini, E.A.; Schleif, W.A.; Quintero, J.C. L-735,524: the design of a potent and orally bioavailable HIV protease inhibitor. J. Med. Chem.,  1994, 37(21), 3443-3451.
[http://dx.doi.org/10.1021/jm00047a001] [PMID:  7932573] 
[135] 
Vacca, J.P.; Dorsey, B.D.; Schleif, W.A.; Levin, R.B.; McDaniel, S.L.; Darke, P.L.; Zugay, J.; Quintero, J.C.; Blahy, O.M.; Roth, E. L-735,524: an orally bioavailable human immunodeficiency virus type 1 protease inhibitor. Proc. Natl. Acad. Sci. USA,  1994, 91(9), 4096-4100.
[http://dx.doi.org/10.1073/pnas.91.9.4096] [PMID:  8171040] 
[136] 
Cohen, J. Protease inhibitors: a tale of two companies. Science,  1996, 272(5270), 1882-1883.
[http://dx.doi.org/10.1126/science.272.5270.1882] [PMID:  8658156] 
[137] 
Lin, J.H.; Ostovic, D.; Vacca, J.P. The integration of medicinal chemistry, drug metabolism, and pharmaceutical research and development in drug discovery and development. The story of Crixivan, an HIV protease inhibitor. Pharm. Biotechnol.,  1998, 11, 233-255.
[http://dx.doi.org/10.1007/0-306-47384-4_11] [PMID:  9760683] 
[138] 
Letendre, S.L.; Zheng, J.C.; Kaul, M.; Yiannoutsos, C.T.; Ellis, R.J.; Taylor, M.J.; Marquie-Beck, J.; Navia, B.; Consortium, H.I.V.N. Chemokines in cerebrospinal fluid correlate with cerebral metabolite patterns in HIV-infected individuals. J. Neurovirol.,  2011, 17(1), 63-69.
[http://dx.doi.org/10.1007/s13365-010-0013-2] [PMID:  21246320] 
[139] 
Hresko, R.C.; Hruz, P.W. HIV protease inhibitors act as competitive inhibitors of the cytoplasmic glucose binding site of GLUTs with differing affinities for GLUT1 and GLUT4. PLoS One,  2011, 6(9)e25237
[http://dx.doi.org/10.1371/journal.pone.0025237] [PMID:  21966466] 
[140] 
Ho, T.T.; Chan, K.C.; Wong, K.H.; Lee, S.S. Indinavir-associated facial lipodystrophy in HIV-infected patients. AIDS Patient Care STDS,  1999, 13(1), 11-16.
[http://dx.doi.org/10.1089/apc.1999.13.11] [PMID:  11362080] 
[141] 
Krautheim, A. Indinavir-associated lipodystrophy Praxis (Bern
1994),,  1999, 88(7), 825-287.
[PMID:  10097649] 
[142] 
Viraben, R.; Aquilina, C. Indinavir-associated lipodystrophy. AIDS,  1998, 12(6), F37-F39.
[http://dx.doi.org/10.1097/00002030-199806000-00001] [PMID:  9583592] 
[143] 
Nadler, R.B.; Rubenstein, J.N.; Eggener, S.E.; Loor, M.M.; Smith, N.D. The etiology of urolithiasis in HIV infected patients. J. Urol.,  2003, 169(2), 475-477.
[http://dx.doi.org/10.1016/S0022-5347(05)63936-5] [PMID:  12544290] 
[144] 
Capaldini, L. Protease inhibitors’ metabolic side effects: cholesterol, triglycerides, blood sugar, and “crix belly”. Interview with Lisa Capaldini, M.D. Interview by John S. James. AIDS Treat. News,  1997, 277, 1-4.
[PMID:  1136455] 
[145] 
González de Requena, D.; Gallego, O.; de Mendoza, C.; Corral, A.; Jiménez-Nácher, I.; Soriano, V. Indinavir plasma concentrations and resistance mutations in patients experiencing early virological failure. AIDS Res. Hum. Retroviruses,  2003, 19(6), 457-459.
[http://dx.doi.org/10.1089/088922203766774496] [PMID:  12882654] 
[146] 
Kaldor, S.W.; Kalish, V.J.; Davies, J.F., II; Shetty, B.V.; Fritz, J.E.; Appelt, K.; Burgess, J.A.; Campanale, K.M.; Chirgadze, N.Y.; Clawson, D.K.; Dressman, B.A.; Hatch, S.D.; Khalil, D.A.; Kosa, M.B.; Lubbehusen, P.P.; Muesing, M.A.; Patick, A.K.; Reich, S.H.; Su, K.S.; Tatlock, J.H. Viracept (nelfinavir mesylate, AG1343): a potent, orally bioavailable inhibitor of HIV-1 protease. J. Med. Chem.,  1997, 40(24), 3979-3985.
[http://dx.doi.org/10.1021/jm9704098] [PMID:  9397180] 
[147] 
Patick, A.K.; Mo, H.; Markowitz, M.; Appelt, K.; Wu, B.; Musick, L.; Kalish, V.; Kaldor, S.; Reich, S.; Ho, D.; Webber, S. Antiviral and resistance studies of AG1343, an orally bioavailable inhibitor of human immunodeficiency virus protease. Antimicrob. Agents Chemother.,  1996, 40(2), 292-297.
[http://dx.doi.org/10.1128/AAC.40.2.292] [PMID:  8834868] 
[148] 
Bardsley-Elliot, A.; Plosker, G.L. Nelfinavir: An update on its use in HIV infection. Drugs,  2000, 59(3), 581-620.
[http://dx.doi.org/10.2165/00003495-200059030-00014] [PMID:  10776836] 
[149] 
Max, B.; Sherer, R. Management of the adverse effects of antiretroviral therapy and medication adherence. Clin. Infect. Dis.,  2000, 30(Suppl. 2), S96-S116.
[http://dx.doi.org/10.1086/313859] [PMID:  10860894] 
[150] 
Livington, D.J.; Pazhanisamy, S.; Porter, D.J.; Partaledis, J.A.; Tung, R.D.; Painter, G.R. Weak binding of VX-478 to human plasma proteins and implications for anti-human immunodeficiency virus therapy. J. Infect. Dis.,  1995, 172(5), 1238-1245.
[http://dx.doi.org/10.1093/infdis/172.5.1238] [PMID:  7594659] 
[151] 
St Clair, M.H.; Millard, J.; Rooney, J.; Tisdale, M.; Parry, N.; Sadler, B.M.; Blum, M.R.; Painter, G. In vitro antiviral activity of 141W94 (VX-478) in combination with other antiretroviral agents. Antiviral Res.,  1996, 29(1), 53-56.
[http://dx.doi.org/10.1016/0166-3542(95)00916-7] [PMID:  8721545] 
[152] 
Tie, Y.; Wang, Y.F.; Boross, P.I.; Chiu, T.Y.; Ghosh, A.K.; Tozser, J.; Louis, J.M.; Harrison, R.W.; Weber, I.T. Critical differences in HIV-1 and HIV-2 protease specificity for clinical inhibitors. Protein Sci.,  2012, 21(3), 339-350.
[http://dx.doi.org/10.1002/pro.2019] [PMID:  22238126] 
[153] 
Dubé, M.P.; Qian, D.; Edmondson-Melançon, H.; Sattler, F.R.; Goodwin, D.; Martinez, C.; Williams, V.; Johnson, D.; Buchanan, T.A. Prospective, intensive study of metabolic changes associated with 48 weeks of amprenavir-based antiretroviral therapy. Clin. Infect. Dis.,  2002, 35(4), 475-481.
[http://dx.doi.org/10.1086/341489] [PMID:  12145733] 
[154] 
Floridia, M.; Bucciardini, R.; Fragola, V.; Galluzzo, C.M.; Giannini, G.; Pirillo, M.F.; Amici, R.; Andreotti, M.; Ricciardulli, D.; Tomino, C.; Vella, S. Risk factors and occurrence of rash in HIV-positive patients not receiving nonnucleoside reverse transcriptase inhibitor: data from a randomized study evaluating use of protease inhibitors in nucleoside-experienced patients with very low CD4 levels (<50 cells/microL). HIV Med.,  2004, 5(1), 1-10.
[http://dx.doi.org/10.1111/j.1468-1293.2004.00177.x] [PMID:  14731162] 
[155] 
Subbaiah, M.A.M.; Meanwell, N.A.; Kadow, J.F. Design strategies in the prodrugs of HIV-1 protease inhibitors to improve the pharmaceutical properties. Eur. J. Med. Chem.,  2017, 139, 865-883.
[http://dx.doi.org/10.1016/j.ejmech.2017.07.044] [PMID:  28865281] 
[156] 
Vierling, P.; Greiner, J. Prodrugs of HIV protease inhibitors. Curr. Pharm. Des.,  2003, 9(22), 1755-1770.
[http://dx.doi.org/10.2174/1381612033454441] [PMID:  12871195] 
[157] 
Torres, H.A.; Arduino, R.C. Fosamprenavir calcium plus ritonavir for HIV infection. Expert Rev. Anti Infect. Ther.,  2007, 5(3), 349-363.
[http://dx.doi.org/10.1586/14787210.5.3.349] [PMID:  17547501] 
[158] 
Gathe, J.C., Jr; Wood, R.; Sanne, I.; DeJesus, E.; Schürmann, D.; Gladysz, A.; Garris, C.; Givens, N.; Elston, R.; Yeo, J. Long-term (120-Week) antiviral efficacy and tolerability of fosamprenavir/ritonavir once daily in therapy-naive patients with HIV-1 infection: an uncontrolled, open-label, single-arm follow-on study. Clin. Ther.,  2006, 28(5), 745-754.
[http://dx.doi.org/10.1016/j.clinthera.2006.05.011] [PMID:  16861096] 
[159] 
Judd, A.; Duong, T.; Galli, L.; Goetghebuer, T.; Ene, L.; Noguera Julian, A.; Ramos Amador, J.T.; Pimenta, J.M.; Thorne, C.; Giaquinto, C.; European, P.; Paediatric, H.I.V.C.C.E. Post-licensing safety of fosamprenavir in HIV-infected children in Europe. Pharmacoepidemiol. Drug Saf.,  2014, 23(3), 321-325.
[http://dx.doi.org/10.1002/pds.3543] [PMID:  24741696] 
[160] 
Sham, H.L.; Kempf, D.J.; Molla, A.; Marsh, K.C.; Kumar, G.N.; Chen, C.M.; Kati, W.; Stewart, K.; Lal, R.; Hsu, A.; Betebenner, D.; Korneyeva, M.; Vasavanonda, S.; McDonald, E.; Saldivar, A.; Wideburg, N.; Chen, X.; Niu, P.; Park, C.; Jayanti, V.; Grabowski, B.; Granneman, G.R.; Sun, E.; Japour, A.J.; Leonard, J.M.; Plattner, J.J.; Norbeck, D.W. ABT-378, a highly potent inhibitor of the human immunodeficiency virus protease. Antimicrob. Agents Chemother.,  1998, 42(12), 3218-3224.
[http://dx.doi.org/10.1128/AAC.42.12.3218] [PMID:  9835517] 
[161] 
Croxtall, J.D.; Perry, C.M. Lopinavir/ritonavir: A review of its use in the management of HIV-1 infection. Drugs,  2010, 70(14), 1885-1915.
[http://dx.doi.org/10.2165/11204950-000000000-00000] [PMID:  20836579] 
[162] 
Chandwani, A.; Shuter, J. Lopinavir/ritonavir in the treatment of HIV-1 infection: a review. Ther. Clin. Risk Manag.,  2008, 4(5), 1023-1033.
[PMID:  19209283] 
[163] 
Oldfield, V.; Plosker, G.L. Lopinavir/ritonavir: A review of its use in the management of HIV infection. Drugs,  2006, 66(9), 1275-1299.
[http://dx.doi.org/10.2165/00003495-200666090-00012] [PMID:  16827606] 
[164] 
Cvetkovic, R.S.; Goa, K.L. Lopinavir/ritonavir: A review of its use in the management of HIV infection. Drugs,  2003, 63(8), 769-802.
[http://dx.doi.org/10.2165/00003495-200363080-00004] [PMID:  12662125] 
[165] 
Noor, M.A.; Parker, R.A.; O’Mara, E.; Grasela, D.M.; Currie, A.; Hodder, S.L.; Fiedorek, F.T.; Haas, D.W. The effects of HIV protease inhibitors atazanavir and lopinavir/ritonavir on insulin sensitivity in HIV-seronegative healthy adults. AIDS,  2004, 18(16), 2137-2144.
[http://dx.doi.org/10.1097/00002030-200411050-00005] [PMID:  15577646] 
[166] 
Cresswell, F.V.; Tomlins, J.; Churchill, D.R.; Walker-Bone, K.; Richardson, D. Achilles tendinopathy following Kaletra (lopinavir/ritonavir) use. Int. J. STD AIDS,  2014, 25(11), 833-835.
[http://dx.doi.org/10.1177/0956462414523403] [PMID:  24516081] 
[167] 
Manfredi, R.; Sabbatani, S. Serious, multi-organ hypersensitivity to lopinavir alone, involving cutaneous-mucous rash, and myeloid, liver, and kidney function. AIDS,  2006, 20(18), 2399-2400.
[http://dx.doi.org/10.1097/QAD.0b013e328010f212] [PMID:  17117031] 
[168] 
Bold, G.; Fässler, A.; Capraro, H.G.; Cozens, R.; Klimkait, T.; Lazdins, J.; Mestan, J.; Poncioni, B.; Rösel, J.; Stover, D.; Tintelnot-Blomley, M.; Acemoglu, F.; Beck, W.; Boss, E.; Eschbach, M.; Hürlimann, T.; Masso, E.; Roussel, S.; Ucci-Stoll, K.; Wyss, D.; Lang, M. New aza-dipeptide analogues as potent and orally absorbed HIV-1 protease inhibitors: candidates for clinical development. J. Med. Chem.,  1998, 41(18), 3387-3401.
[http://dx.doi.org/10.1021/jm970873c] [PMID:  9719591] 
[169] 
Becker, S. Atazanavir: improving the HIV protease inhibitor class. Expert Rev. Anti Infect. Ther.,  2003, 1(3), 403-413.
[http://dx.doi.org/10.1586/14787210.1.3.403] [PMID:  15482137] 
[170] 
Squires, K.; Lazzarin, A.; Gatell, J.M.; Powderly, W.G.; Pokrovskiy, V.; Delfraissy, J.F.; Jemsek, J.; Rivero, A.; Rozenbaum, W.; Schrader, S.; Sension, M.; Vibhagool, A.; Thiry, A.; Giordano, M. Comparison of once-daily atazanavir with efavirenz, each in combination with fixed-dose zidovudine and lamivudine, as initial therapy for patients infected with HIV. J. Acquir. Immune Defic. Syndr.,  2004, 36(5), 1011-1019.
[http://dx.doi.org/10.1097/00126334-200408150-00003] [PMID:  15247553] 
[171] 
Murphy, R.L.; Sanne, I.; Cahn, P.; Phanuphak, P.; Percival, L.; Kelleher, T.; Giordano, M. Dose-ranging, randomized, clinical trial of atazanavir with lamivudine and stavudine in antiretroviral-naive subjects: 48-week results. AIDS,  2003, 17(18), 2603-2614.
[http://dx.doi.org/10.1097/00002030-200312050-00007] [PMID:  14685054] 
[172] 
Cahn, P.E.; Gatell, J.M.; Squires, K.; Percival, L.D.; Piliero, P.J.; Sanne, I.A.; Shelton, S.; Lazzarin, A.; Odeshoo, L.; Kelleher, T.D.; Thiry, A.; Giordano, M.D.; Schnittman, S.M. Atazanavir--a once-daily HIV protease inhibitor that does not cause dyslipidemia in newly treated patients: results from two randomized clinical trials. J. Int. Assoc. Physicians AIDS Care (Chic.),  2004, 3(3), 92-98.
[http://dx.doi.org/10.1177/154510970400300304] [PMID:  15573713] 
[173] 
Simplified HIV therapy. Atazanavir: the first protease inhibitor with once daily administration. MMW Fortschr. Med.,  2004, 146(Spec No 1), 14-16.
[PMID:  15373035] 
[174] 
Dauchy, F.A.; Lawson-Ayayi, S.; de La Faille, R.; Bonnet, F.; Rigothier, C.; Mehsen, N.; Miremont-Salamé, G.; Cazanave, C.; Greib, C.; Dabis, F.; Dupon, M. Increased risk of abnormal proximal renal tubular function with HIV infection and antiretroviral therapy. Kidney Int.,  2011, 80(3), 302-309.
[http://dx.doi.org/10.1038/ki.2011.124] [PMID:  21544066] 
[175] 
Calza, L.; Trapani, F.; Salvadori, C.; Magistrelli, E.; Manfredi, R.; Colangeli, V.; Di Bari, M.A.; Borderi, M.; Viale, P. Incidence of renal toxicity in HIV-infected, antiretroviral-naïve patients starting tenofovir/emtricitabine associated with efavirenz, atazanavir/ritonavir, or lopinavir/ritonavir. Scand. J. Infect. Dis.,  2013, 45(2), 147-154.
[http://dx.doi.org/10.3109/00365548.2012.712213] [PMID:  22991923] 
[176] 
Le Tiec, C.; Barrail, A.; Goujard, C.; Taburet, A.M. Clinical pharmacokinetics and summary of efficacy and tolerability of atazanavir. Clin. Pharmacokinet.,  2005, 44(10), 1035-1050.
[http://dx.doi.org/10.2165/00003088-200544100-00003] [PMID:  16176117] 
[177] 
Poppe, S.M.; Slade, D.E.; Chong, K.T.; Hinshaw, R.R.; Pagano, P.J.; Markowitz, M.; Ho, D.D.; Mo, H.; Gorman, R.R., III; Dueweke, T.J.; Thaisrivongs, S.; Tarpley, W.G. Antiviral activity of the dihydropyrone PNU-140690, a new nonpeptidic human immunodeficiency virus protease inhibitor. Antimicrob. Agents Chemother.,  1997, 41(5), 1058-1063.
[http://dx.doi.org/10.1128/AAC.41.5.1058] [PMID:  9145869] 
[178] 
Kandula, V.R.; Khanlou, H.; Farthing, C. Tipranavir: a novel second-generation nonpeptidic protease inhibitor. Expert Rev. Anti Infect. Ther.,  2005, 3(1), 9-21.
[http://dx.doi.org/10.1586/14787210.3.1.9] [PMID:  15757454] 
[179] 
King, J.R.; Acosta, E.P. Tipranavir: a novel nonpeptidic protease inhibitor of HIV. Clin. Pharmacokinet.,  2006, 45(7), 665-682.
[http://dx.doi.org/10.2165/00003088-200645070-00003] [PMID:  16802849] 
[180] 
Rusconi, S.; La Seta Catamancio, S.; Citterio, P.; Kurtagic, S.; Violin, M.; Balotta, C.; Moroni, M.; Galli, M.; d’Arminio-Monforte, A. Susceptibility to PNU-140690 (Tipranavir) of human immunodeficiency virus type 1 isolates derived from patients with multidrug resistance to other protease inhibitors. Antimicrob. Agents Chemother.,  2000, 44(5), 1328-1332.
[http://dx.doi.org/10.1128/AAC.44.5.1328-1332.2000] [PMID:  10770770] 
[181] 
Larder, B.A.; Hertogs, K.; Bloor, S.; van den Eynde, C.H.; DeCian, W.; Wang, Y.; Freimuth, W.W.; Tarpley, G. Tipranavir inhibits broadly protease inhibitor-resistant HIV-1 clinical samples. AIDS,  2000, 14(13), 1943-1948.
[http://dx.doi.org/10.1097/00002030-200009080-00009] [PMID:  10997398] 
[182] 
Macías, J.; Orihuela, F.; Rivero, A.; Viciana, P.; Márquez, M.; Portilla, J.; Ríos, M.J.; Muñoz, L.; Pasquau, J.; Castaño, M.A.; Abdel-Kader, L.; Pineda, J.A. Hepatic safety of tipranavir plus ritonavir (TPV/r)-based antiretroviral combinations: Effect of hepatitis virus co-infection and pre-existing fibrosis. J. Antimicrob. Chemother.,  2009, 63(1), 178-183.
[http://dx.doi.org/10.1093/jac/dkn429] [PMID:  18952618] 
[183] 
Arbuthnot, C.; Wilde, J.T. Increased risk of bleeding with the use of tipranavir boosted with ritonavir in haemophilic patients. Haemophilia,  2008, 14(1), 140-141.
[PMID:  18184260] 
[184] 
MacArthur, R.D. Darunavir: promising initial results. Lancet,  2007, 369(9568), 1143-1144.
[http://dx.doi.org/10.1016/S0140-6736(07)60499-1] [PMID:  17416241] 
[185] 
FDA approves new HIV treatment for patients who do not respond to existing drugs.  http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2006/ucm108676.html(Accessed 2006)., 
[186] 
Koh, Y.; Nakata, H.; Maeda, K.; Ogata, H.; Bilcer, G.; Devasamudram, T.; Kincaid, J.F.; Boross, P.; Wang, Y.F.; Tie, Y.; Volarath, P.; Gaddis, L.; Harrison, R.W.; Weber, I.T.; Ghosh, A.K.; Mitsuya, H. Novel bis-tetrahydrofuranylurethane-containing nonpeptidic protease inhibitor (PI) UIC-94017 (TMC114) with potent activity against multi-PI-resistant human immunodeficiency virus in vitro. Antimicrob. Agents Chemother.,  2003, 47(10), 3123-3129.
[http://dx.doi.org/10.1128/AAC.47.10.3123-3129.2003] [PMID:  14506019] 
[187] 
Yoshimura, K.; Kato, R.; Kavlick, M.F.; Nguyen, A.; Maroun, V.; Maeda, K.; Hussain, K.A.; Ghosh, A.K.; Gulnik, S.V.; Erickson, J.W.; Mitsuya, H. A potent human immunodeficiency virus type 1 protease inhibitor, UIC-94003 (TMC-126), and selection of a novel (A28S) mutation in the protease active site. J. Virol.,  2002, 76(3), 1349-1358.
[http://dx.doi.org/10.1128/JVI.76.3.1349-1358.2002] [PMID:  11773409] 
[188] 
Prabu-Jeyabalan, M.; Nalivaika, E.; Schiffer, C.A. How does a symmetric dimer recognize an asymmetric substrate? A substrate complex of HIV-1 protease. J. Mol. Biol.,  2000, 301(5), 1207-1220.
[http://dx.doi.org/10.1006/jmbi.2000.4018] [PMID:  10966816] 
[189] 
Brower, E.T.; Bacha, U.M.; Kawasaki, Y.; Freire, E. Inhibition of HIV-2 protease by HIV-1 protease inhibitors in clinical use. Chem. Biol. Drug Des.,  2008, 71(4), 298-305.
[http://dx.doi.org/10.1111/j.1747-0285.2008.00647.x] [PMID:  18312292] 
[190] 
King, N.M.; Prabu-Jeyabalan, M.; Nalivaika, E.A.; Wigerinck, P.; de Béthune, M.P.; Schiffer, C.A. Structural and thermodynamic basis for the binding of TMC114, a next-generation human immunodeficiency virus type 1 protease inhibitor. J. Virol.,  2004, 78(21), 12012-12021.
[http://dx.doi.org/10.1128/JVI.78.21.12012-12021.2004] [PMID:  15479840] 
[191] 
Dierynck, I.; De Wit, M.; Gustin, E.; Keuleers, I.; Vandersmissen, J.; Hallenberger, S.; Hertogs, K. Binding kinetics of darunavir to human immunodeficiency virus type 1 protease explain the potent antiviral activity and high genetic barrier. J. Virol.,  2007, 81(24), 13845-13851.
[http://dx.doi.org/10.1128/JVI.01184-07] [PMID:  17928344] 
[192] 
Chellappan, S.; Kiran Kumar Reddy, G.S.; Ali, A.; Nalam, M.N.; Anjum, S.G.; Cao, H.; Kairys, V.; Fernandes, M.X.; Altman, M.D.; Tidor, B.; Rana, T.M.; Schiffer, C.A.; Gilson, M.K. Design of mutation-resistant HIV protease inhibitors with the substrate envelope hypothesis. Chem. Biol. Drug Des.,  2007, 69(5), 298-313.
[http://dx.doi.org/10.1111/j.1747-0285.2007.00514.x] [PMID:  17539822] 
[193] 
Kovalevsky, A.Y.; Liu, F.; Leshchenko, S.; Ghosh, A.K.; Louis, J.M.; Harrison, R.W.; Weber, I.T. Ultra-high resolution crystal structure of HIV-1 protease mutant reveals two binding sites for clinical inhibitor TMC114. J. Mol. Biol.,  2006, 363(1), 161-173.
[http://dx.doi.org/10.1016/j.jmb.2006.08.007] [PMID:  16962136] 
[194] 
Kovalevsky, A.Y.; Ghosh, A.K.; Weber, I.T. Solution kinetics measurements suggest HIV-1 protease has two binding sites for darunavir and amprenavir. J. Med. Chem.,  2008, 51(20), 6599-6603.
[http://dx.doi.org/10.1021/jm800283k] [PMID:  18808097] 
[195] 
Deeks, E.D. Darunavir: A review of its use in the management of HIV-1 infection. Drugs,  2014, 74(1), 99-125.
[http://dx.doi.org/10.1007/s40265-013-0159-3] [PMID:  24338166] 
[196] 
Molina, J.M.; Cohen, C.; Katlama, C.; Grinsztejn, B.; Timerman, A. Pedro, Rde.J.; Vangeneugden, T.; Miralles, D.; Meyer, S.D.; Parys, W.; Lefebvre, E. Safety and efficacy of darunavir (TMC114) with low-dose ritonavir in treatment-experienced patients: 24-week results of POWER 3. J. Acquir. Immune Defic. Syndr.,  2007, 46(1), 24-31.
[http://dx.doi.org/10.1097/QAI.0b013e3181359cfb] [PMID:  17621237] 
[197] 
European commission approves symtuza® for the treatment of
	HIV-1 in adults and adolescents in europe. Janssen press statement https://www.jnj.com/mediacenter/press-releases/european-comm-ission-approves-symtuza-for-the-treatment-of-hiv-1-in-adults-and-adolescents-in-europe (Accessed 2017).
[198] 
Orkin, C. Week 48 results of AMBER: A phase 3, randomised, doubleblind trial in antiretroviral treatment (ART)-naive HIV-1-infected adults to evaluate the efficacy and safety of the once-daily, single-tablet regimen (STR) of darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) versus darunavir/cobicistat (DRV/c) plus emtricitabine/tenofovir disoproxil fumarate (FTC/TDF). AIDS,  2017, 32(11), 1431-1442.
[http://dx.doi.org/10.1097/QAD.0000000000001817] 
[199] 
Link, J.O.; Katto, D.; Moore, M.; Mulato, A.; Murray, B.; Mwangi, J.; Shapiro, N.D.; Stepan, G.; Wang, Y.; Yang, Z-Y. In:
Abstract 433, Novel HIV PI with high resistance barrier and potential
for unboosted QD oral dosing, The Conference on Retroviruses
and Opportunistic Infections (CROI), Seattle, USA, February 13–
16, 2017; Gilead Scis, Inc: Foster City, CA, USA, 2017.
[200] 
Dandache, S.; Sévigny, G.; Yelle, J.; Stranix, B.R.; Parkin, N.; Schapiro, J.M.; Wainberg, M.A.; Wu, J.J. In vitro antiviral activity and cross-resistance profile of PL-100, a novel protease inhibitor of human immunodeficiency virus type 1. Antimicrob. Agents Chemother.,  2007, 51(11), 4036-4043.
[http://dx.doi.org/10.1128/AAC.00149-07] [PMID:  17638694] 
[201] 
Nalam, M.N.; Peeters, A.; Jonckers, T.H.; Dierynck, I.; Schiffer, C.A. Crystal structure of lysine sulfonamide inhibitor reveals the displacement of the conserved flap water molecule in human immunodeficiency virus type 1 protease. J. Virol.,  2007, 81(17), 9512-9518.
[http://dx.doi.org/10.1128/JVI.00799-07] [PMID:  17596316] 
[202] 
Asahchop, E.L.; Oliveira, M.; Quashie, P.K.; Moisi, D.; Martinez-Cajas, J.L.; Brenner, B.G.; Tremblay, C.L.; Wainberg, M.A. In vitro and structural evaluation of PL-100 as a potential second-generation HIV-1 protease inhibitor. J. Antimicrob. Chemother.,  2013, 68(1), 105-112.
[http://dx.doi.org/10.1093/jac/dks342] [PMID:  22945918] 
[203] 
Dandache, S.; Coburn, C.A.; Oliveira, M.; Allison, T.J.; Holloway, M.K.; Wu, J.J.; Stranix, B.R.; Panchal, C.; Wainberg, M.A.; Vacca, J.P. PL-100, a novel HIV-1 protease inhibitor displaying a high genetic barrier to resistance: An in vitro selection study. J. Med. Virol.,  2008, 80(12), 2053-2063.
[http://dx.doi.org/10.1002/jmv.21329] [PMID:  19040279] 
[204] 
Study of the Safety. Tolerability and pharmacokinetics of TMB-
607 in HIV-negative volunteers. ClinicalTrials.gov, 2017.(Available
at:. https://clinicaltrials.gov/ct2/show/NCT03110549
[205] 
Pharmacokinetics, safety & tolerability of isotopologs of atazanavir
(ATV), with pharmacokinetic comparison to reyataz. ClinicalTrials.gov Identifier: NCT01458769, (Available at: https://clinicaltrials.gov/ct2/show/NCT01458769(Accessed on. 2013.
[206] 
Holland, A.; Corp, C.; Wynne, B.; Ruff, D.; Guttendorf, R. A first
in human study evaluating the safety, tolerability, and pharmacokinetics
(PK) of SPI-256, a novel HIV protease inhibitor (PI), administered
alone and in combination with ritonavir (RTV) in healthy
adult subjects. Poster presented at the 48th Annual ICAAC/46th
Annual IDSA Meeting, 2008, October 25–28; 2008; Washington,
DC. (Accessed on March 4, 2019 at https://idsa.confex.com/idsa/2008/webprogram/Paper27600.html)
[207] 
Gulnik, S.V.; Eissenstat, M. Approaches to the design of HIV protease inhibitors with improved resistance profiles. Curr. Opin. HIV AIDS,  2008, 3(6), 633-641.
[http://dx.doi.org/10.1097/COH.0b013e328313911d] [PMID:  19373035] 
[208] 
Hartman, T.L.; Buckheit, R.W., Jr The continuing evolution of HIV-1 therapy: Identification and development of novel antiretroviral agents targeting viral and cellular targets. Mol. Biol. Int.,  2012, 2012401965
[http://dx.doi.org/10.1155/2012/401965] [PMID:  22848825] 
[209] 
Cihlar, T.; He, G.X.; Liu, X.; Chen, J.M.; Hatada, M.; Swaminathan, S.; McDermott, M.J.; Yang, Z.Y.; Mulato, A.S.; Chen, X.; Leavitt, S.A.; Stray, K.M.; Lee, W.A. Suppression of HIV-1 protease inhibitor resistance by phosphonate-mediated solvent anchoring. J. Mol. Biol.,  2006, 363(3), 635-647.
[http://dx.doi.org/10.1016/j.jmb.2006.07.073] [PMID:  16979654] 
[210] 
Callebaut, C.; Stray, K.; Tsai, L.; Williams, M.; Yang, Z.Y.; Cannizzaro, C.; Leavitt, S.A.; Liu, X.; Wang, K.; Murray, B.P.; Mulato, A.; Hatada, M.; Priskich, T.; Parkin, N.; Swaminathan, S.; Lee, W.; He, G.X.; Xu, L.; Cihlar, T. In vitro characterization of GS-8374, a novel phosphonate-containing inhibitor of HIV-1 protease with a favorable resistance profile. Antimicrob. Agents Chemother.,  2011, 55(4), 1366-1376.
[http://dx.doi.org/10.1128/AAC.01183-10] [PMID:  21245449] 
[211] 
López-Otín, C.; Bond, J.S. Proteases: multifunctional enzymes in life and disease. J. Biol. Chem.,  2008, 283(45), 30433-30437.
[http://dx.doi.org/10.1074/jbc.R800035200] [PMID:  18650443] 
[212] 
Drag, M.; Salvesen, G.S. Emerging principles in protease-based drug discovery. Nat. Rev. Drug Discov.,  2010, 9(9), 690-701.
[http://dx.doi.org/10.1038/nrd3053] [PMID:  20811381] 
[213] 
Lv, Z.; Chu, Y.; Wang, Y. HIV protease inhibitors: A review of molecular selectivity and toxicity. HIV AIDS (Auckl.),  2015, 7, 95-104.
[PMID:  25897264] 
[214] 
Brik, A.; Wong, C.H. HIV-1 protease: Mechanism and drug discovery. Org. Biomol. Chem.,  2003, 1(1), 5-14.
[http://dx.doi.org/10.1039/b208248a] [PMID:  12929379] 
[215] 
Chaudhury, S.; Gray, J.J. Identification of structural mechanisms of HIV-1 protease specificity using computational peptide docking: implications for drug resistance. Structure,  2009, 17(12), 1636-1648.
[http://dx.doi.org/10.1016/j.str.2009.10.008] [PMID:  20004167] 
[216] 
King, J.R.; Wynn, H.; Brundage, R.; Acosta, E.P. Pharmacokinetic enhancement of protease inhibitor therapy. Clin. Pharmacokinet.,  2004, 43(5), 291-310.
[http://dx.doi.org/10.2165/00003088-200443050-00003] [PMID:  15080763] 
[217] 
Flexner, C. HIV-protease inhibitors. N. Engl. J. Med.,  1998, 338(18), 1281-1292.
[http://dx.doi.org/10.1056/NEJM199804303381808] [PMID:  9562584] 
[218] 
Flexner, C.W. Antiretroviral agents and treatment of HIV infection In: Goodman & Gilman's The Pharmacological Basis of Therapeutics The McGraw-Hill Companies, Inc., United States; , 2011. 
[http://dx.doi.org/10.1036/0071422803] 
[219] 
Lexi-Comp, Inc. Drug information handbook. ( 27th Ed.), Lexi-Comp, Hudson, OH., Wolters Kluwer,  , 2018. 
[220] 
McEvoy, G.K. S.E.; Kester, L.; Litvak, K.; Miller, J.; Welsh, OH. AHFS 2015 Drug Information; American Society of Health-System Pharmacists: Bethesda, Maryland, United States, 2015. 
[221] 
Vella, S.; Floridia, M. Saquinavir. Clinical pharmacology and efficacy. Clin. Pharmacokinet.,  1998, 34(3), 189-201.
[http://dx.doi.org/10.2165/00003088-199834030-00002] [PMID:  9533981] 
[222] 
Kravcik, S. Pharmacology and clinical experience with saquinavir. Expert Opin. Pharmacother.,  2001, 2(2), 303-315.
[http://dx.doi.org/10.1517/14656566.2.2.303] [PMID:  11336588] 
[223] 
AIDSInfo. 2019. (Avaiable at:  2019.https://aidsinfo.nih.gov/drugs/164/saquinavir/35/professional
[224] 
Zha, W.; Zha, B.S.; Zhou, F.; Zhou, H.; Wang, G. The cellular pharmacokinetics of HIV protease inhibitors: current knowledge and future perspectives. Curr. Drug Metab.,  2012, 13(8), 1174-1183.
[http://dx.doi.org/10.2174/138920012802850119] [PMID:  22746305] 
[225] 
Hsu, A.; Granneman, G.R.; Bertz, R.J. Ritonavir. Clinical pharmacokinetics and interactions with other anti-HIV agents. Clin. Pharmacokinet.,  1998, 35(4), 275-291.
[http://dx.doi.org/10.2165/00003088-199835040-00002] [PMID:  9812178] 
[226] 
AIDSInfo. https://aidsinfo.nih.gov/drugs/244/ritonavir/0/patient (Accessed 2019).
[227] 
Csajka, C.; Marzolini, C.; Fattinger, K.; Décosterd, L.A.; Telenti, A.; Biollaz, J.; Buclin, T. Population pharmacokinetics of indinavir in patients infected with human immunodeficiency virus. Antimicrob. Agents Chemother.,  2004, 48(9), 3226-3232.
[http://dx.doi.org/10.1128/AAC.48.9.3226-3232.2004] [PMID:  15328077] 
[228] 
Hoetelmans, R.M.; Meenhorst, P.L.; Mulder, J.W.; Burger, D.M.; Koks, C.H.; Beijnen, J.H. Clinical pharmacology of HIV protease inhibitors: Focus on saquinavir, indinavir, and ritonavir. Pharm. World Sci.,  1997, 19(4), 159-175.
[http://dx.doi.org/10.1023/A:1008629608556] [PMID:  9297727] 
[229] 
Pai, V.B.; Nahata, M.C. Nelfinavir mesylate: A protease inhibitor. Ann. Pharmacother.,  1999, 33(3), 325-339.
[http://dx.doi.org/10.1345/aph.18089] [PMID:  10200859] 
[230] 
Sadler, B.M.; Stein, D.S. Clinical pharmacology and pharmacokinetics of amprenavir. Ann. Pharmacother.,  2002, 36(1), 102-118.
[http://dx.doi.org/10.1345/aph.10423] [PMID:  11816239] 
[231] 
Bentué-Ferrer, D.; Arvieux, C.; Tribut, O.; Ruffault, A.; Bellissant, E. Clinical pharmacology, efficacy and safety of atazanavir: a review. Expert Opin. Drug Metab. Toxicol.,  2009, 5(11), 1455-1468.
[http://dx.doi.org/10.1517/17425250903321514] [PMID:  19863454] 
[232] 
Colombo, S.; Buclin, T.; Cavassini, M.; Décosterd, L.A.; Telenti, A.; Biollaz, J.; Csajka, C. Population pharmacokinetics of atazanavir in patients with human immunodeficiency virus infection. Antimicrob. Agents Chemother.,  2006, 50(11), 3801-3808.
[http://dx.doi.org/10.1128/AAC.00098-06] [PMID:  16940065] 
[233] 
AIDSInfo. 2019. (Available at:  https://aidsinfo.nih.gov/drugs/314/atazanavir/0/patient
[234] 
Wire, M.B.; Shelton, M.J.; Studenberg, S. Fosamprenavir: Clinical pharmacokinetics and drug interactions of the amprenavir prodrug. Clin. Pharmacokinet.,  2006, 45(2), 137-168.
[http://dx.doi.org/10.2165/00003088-200645020-00002] [PMID:  16485915] 
[235] 
AIDSInfo. https://aidsinfo.nih.gov/drugs/337/fosamprenavir/0/patient (Accessed 2019).
[236] 
AIDSInfo.  https://aidsinfo.nih.gov/drugs/351/tipranavir/0/patient (Accessed 2019).
[237] 
Rittweger, M.; Arastéh, K. Clinical pharmacokinetics of darunavir. Clin. Pharmacokinet.,  2007, 46(9), 739-756.
[http://dx.doi.org/10.2165/00003088-200746090-00002] [PMID:  17713972] 
[238] 
Ruela Corrêa, J.C.; D’Arcy, D.M.; dos Reis Serra, C.H.; Nunes Salgado, H.R. Darunavir: A critical review of its properties, use and drug interactions. Pharmacology,  2012, 90(1-2), 102-109.
[http://dx.doi.org/10.1159/000339862] [PMID:  22797653] 
[239] 
AIDSInfo. https://aidsinfo.nih.gov/drugs/397/darunavir/0/patient (Accessed 2019).
[240] 
Drug-Drug Interactions. Drug-Drug Interactions: Drug Interactions between Protease Inhibitors and Other Drugs. https://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv/284/pi-drug-interactions (Accessed 2018).
[241] 
Okulicz, J.F. Common Drug Interactions with Protease Inhibitors., https://emedicine. medscape.com/article/2041624-overview (Accessed	on 2019).
[242] 
High-Alert Medications in Community/Ambulatory Settings. In:	Institute for Safe Medication Practices.  https://www.ismp.org/recommendations/high-alert-medications-community-ambulatory-list (Accessed 2011).
[243] 
Levinson, W.  Antiviral drugs: Review of medical microbilogy and
immunology.  In: McGraw-Hill's Medicine and Health; 13th ed;
New York, NY,. , 2014. 
[244] 
Molla, A.; Vasavanonda, S.; Kumar, G.; Sham, H.L.; Johnson, M.; Grabowski, B.; Denissen, J.F.; Kohlbrenner, W.; Plattner, J.J.; Leonard, J.M.; Norbeck, D.W.; Kempf, D.J. Human serum attenuates the activity of protease inhibitors toward wild-type and mutant human immunodeficiency virus. Virology,  1998, 250(2), 255-262.
[http://dx.doi.org/10.1006/viro.1998.9383] [PMID:  9792836] 
[245] 
Kotler, D.P. HIV and antiretroviral therapy: lipid abnormalities and associated cardiovascular risk in HIV-infected patients. J. Acquir. Immune Defic. Syndr.,  2008, 49(Suppl. 2), S79-S85.
[http://dx.doi.org/10.1097/QAI.0b013e318186519c] [PMID:  18725816] 
[246] 
Tebas, P. Insulin resistance and diabetes mellitus associated with antiretroviral use in HIV-infected patients: pathogenesis, prevention, and treatment options. J. Acquir. Immune Defic. Syndr.,  2008, 49(Suppl. 2), S86-S92.
[http://dx.doi.org/10.1097/QAI.0b013e31818651e6] [PMID:  18725817] 
[247] 
Grinspoon, S.; Carr, A. Cardiovascular risk and body-fat abnormalities in HIV-infected adults. N. Engl. J. Med.,  2005, 352(1), 48-62.
[http://dx.doi.org/10.1056/NEJMra041811] [PMID:  15635112] 
[248] 
Riddle, T.M.; Kuhel, D.G.; Woollett, L.A.; Fichtenbaum, C.J.; Hui, D.Y. HIV protease inhibitor induces fatty acid and sterol biosynthesis in liver and adipose tissues due to the accumulation of activated sterol regulatory element-binding proteins in the nucleus. J. Biol. Chem.,  2001, 276(40), 37514-37519.
[http://dx.doi.org/10.1074/jbc.M104557200] [PMID:  11546771] 
[249] 
Carr, A.; Ritzhaupt, A.; Zhang, W.; Zajdenverg, R.; Workman, C.; Gatell, J.M.; Cahn, P.; Chaves, R. Effects of boosted tipranavir and lopinavir on body composition, insulin sensitivity and adipocytokines in antiretroviral-naive adults. AIDS,  2008, 22(17), 2313-2321.
[http://dx.doi.org/10.1097/QAD.0b013e328315a7a5] [PMID:  18981770] 
[250] 
Guaraldi, G.; Stentarelli, C.; Zona, S.; Santoro, A. HIV-associated lipodystrophy: impact of antiretroviral therapy. Drugs,  2013, 73(13), 1431-1450.
[http://dx.doi.org/10.1007/s40265-013-0108-1] [PMID:  24002702] 
[251] 
de Waal, R.; Cohen, K.; Maartens, G. Systematic review of antiretroviral-associated lipodystrophy: Lipoatrophy, but not central fat gain, is an antiretroviral adverse drug reaction. PLoS One,  2013, 8(5)e63623
[http://dx.doi.org/10.1371/journal.pone.0063623] [PMID:  23723990] 
[252] 
Adverse Effects of Antiretroviral Agents. https://aidsinfo.nih.gov (Accessed 2018).
[253] 
Tang, M.W.; Shafer, R.W. HIV-1 antiretroviral resistance: scientific principles and clinical applications. Drugs,  2012, 72(9), e1-e25.
[http://dx.doi.org/10.2165/11633630-000000000-00000] [PMID:  22686620] 
[254] 
Kozal, M. Cross-resistance patterns among HIV protease inhibitors. AIDS Patient Care STDS,  2004, 18(4), 199-208.
[http://dx.doi.org/10.1089/108729104323038874] [PMID:  15142350] 
[255] 
Wensing, A.M.; Calvez, V.; Günthard, H.F.; Johnson, V.A.; Paredes, R.; Pillay, D.; Shafer, R.W.; Richman, D.D. 2017 Update of the drug resistance mutations in HIV-1. Top. Antivir. Med.,  2017, 24(4), 132-133.
[PMID:  28208121] 
[256] 
Liu, T.F.; Shafer, R.W. Web resources for HIV type 1 genotypic-resistance test interpretation. Clin. Infect. Dis.,  2006, 42(11), 1608-1618.
[http://dx.doi.org/10.1086/503914] [PMID:  16652319] 
[257] 
Shafer, R.W.; Rhee, S.Y.; Pillay, D.; Miller, V.; Sandstrom, P.; Schapiro, J.M.; Kuritzkes, D.R.; Bennett, D. HIV-1 protease and reverse transcriptase mutations for drug resistance surveillance. AIDS,  2007, 21(2), 215-223.
[http://dx.doi.org/10.1097/QAD.0b013e328011e691] [PMID:  17197813] 
[258] 
P.I., Resistance Notes In:HIV Drug Resistance Database; https://hivdb.stanford.edu/dr-summary/resistancenotes/PI/ (Accessed	2019).
[259] 
Colonno, R.; Rose, R.; McLaren, C.; Thiry, A.; Parkin, N.; Friborg, J. Identification of I50L as the signature atazanavir (ATV)-resistance mutation in treatment-naive HIV-1-infected patients receiving ATV-containing regimens. J. Infect. Dis.,  2004, 189(10), 1802-1810.
[http://dx.doi.org/10.1086/386291] [PMID:  15122516] 
[260] 
Sista, P.; Wasikowski, B.; Lecocq, P.; Pattery, T.; Bacheler, L. The HIV-1 protease resistance mutation I50L is associated with resistance to atazanavir and susceptibility to other protease inhibitors in multiple mutational contexts. J. Clin. Virol.,  2008, 42(4), 405-408.
[http://dx.doi.org/10.1016/j.jcv.2008.03.023] [PMID:  18472298] 
[261] 
Weinheimer, S.; Discotto, L.; Friborg, J.; Yang, H.; Colonno, R. Atazanavir signature I50L resistance substitution accounts for unique phenotype of increased susceptibility to other protease inhibitors in a variety of human immunodeficiency virus type 1 genetic backbones. Antimicrob. Agents Chemother.,  2005, 49(9), 3816-3824.
[http://dx.doi.org/10.1128/AAC.49.9.3816-3824.2005] [PMID:  16127058] 
[262] 
Yanchunas, J., Jr; Langley, D.R.; Tao, L.; Rose, R.E.; Friborg, J.; Colonno, R.J.; Doyle, M.L. Molecular basis for increased susceptibility of isolates with atazanavir resistance-conferring substitution I50L to other protease inhibitors. Antimicrob. Agents Chemother.,  2005, 49(9), 3825-3832.
[http://dx.doi.org/10.1128/AAC.49.9.3825-3832.2005] [PMID:  16127059] 
[263] 
Ziermann, R.; Limoli, K.; Das, K.; Arnold, E.; Petropoulos, C.J.; Parkin, N.T. A mutation in human immunodeficiency virus type 1 protease, N88S, that causes in vitro hypersensitivity to amprenavir. J. Virol.,  2000, 74(9), 4414-4419.
[http://dx.doi.org/10.1128/JVI.74.9.4414-4419.2000] [PMID:  10756056] 
[264] 
Paulsen, D.; Elston, R.; Snowden, W.; Tisdale, M.; Ross, L. Differentiation of genotypic resistance profiles for amprenavir and lopinavir, a valuable aid for choice of therapy in protease inhibitor-experienced HIV-1-infected subjects. J. Antimicrob. Chemother.,  2003, 52(3), 319-323.
[http://dx.doi.org/10.1093/jac/dkg392] [PMID:  12917233] 
[265] 
De Meyer, S.; Lathouwers, E.; Dierynck, I.; De Paepe, E.; Van Baelen, B.; Vangeneugden, T.; Spinosa-Guzman, S.; Lefebvre, E.; Picchio, G.; de Béthune, M.P. Characterization of virologic failure patients on darunavir/ritonavir in treatment-experienced patients. AIDS,  2009, 23(14), 1829-1840.
[http://dx.doi.org/10.1097/QAD.0b013e32832cbcec] [PMID:  19474650] 
[266] 
de Meyer, S.; Vangeneugden, T.; van Baelen, B.; de Paepe, E.; van Marck, H.; Picchio, G.; Lefebvre, E.; de Béthune, M.P. Resistance profile of darunavir: combined 24-week results from the POWER trials. AIDS Res. Hum. Retroviruses,  2008, 24(3), 379-388.
[http://dx.doi.org/10.1089/aid.2007.0173] [PMID:  18327986] 
[267] 
Delaugerre, C.; Pavie, J.; Palmer, P.; Ghosn, J.; Blanche, S.; Roudiere, L.; Dominguez, S.; Mortier, E.; Molina, J.M.; de Truchis, P. Pattern and impact of emerging resistance mutations in treatment experienced patients failing darunavir-containing regimen. AIDS,  2008, 22(14), 1809-1813.
[http://dx.doi.org/10.1097/QAD.0b013e328307f24a] [PMID:  18690163] 
[268] 
Sterrantino, G.; Zaccarelli, M.; Colao, G.; Baldanti, F.; Di Giambenedetto, S.; Carli, T.; Maggiolo, F.; Zazzi, M.; Group, A.D.S. Genotypic resistance profiles associated with virological failure to darunavir-containing regimens: a cross-sectional analysis. Infection,  2012, 40(3), 311-318.
[http://dx.doi.org/10.1007/s15010-011-0237-y] [PMID:  22237471] 
[269] 
Young, T.P.; Parkin, N.T.; Stawiski, E.; Pilot-Matias, T.; Trinh, R.; Kempf, D.J.; Norton, M. Prevalence, mutation patterns, and effects on protease inhibitor susceptibility of the L76V mutation in HIV-1 protease. Antimicrob. Agents Chemother.,  2010, 54(11), 4903-4906.
[http://dx.doi.org/10.1128/AAC.00906-10] [PMID:  20805393] 
[270] 
Llibre, J.M.; Schapiro, J.M.; Clotet, B. Clinical implications of genotypic resistance to the newer antiretroviral drugs in HIV-1-infected patients with virological failure. Clin. Infect. Dis.,  2010, 50(6), 872-881.
[http://dx.doi.org/10.1086/650732] [PMID:  20158400] 
[271] 
Lambert-Niclot, S.; Flandre, P.; Canestri, A.; Peytavin, G.; Blanc, C.; Agher, R.; Soulié, C.; Wirden, M.; Katlama, C.; Calvez, V.; Marcelin, A.G. Factors associated with the selection of mutations conferring resistance to protease inhibitors (PIs) in PI-experienced patients displaying treatment failure on darunavir. Antimicrob. Agents Chemother.,  2008, 52(2), 491-496.
[http://dx.doi.org/10.1128/AAC.00909-07] [PMID:  18039922] 
[272] 
Maguire, M.; Shortino, D.; Klein, A.; Harris, W.; Manohitharajah, V.; Tisdale, M.; Elston, R.; Yeo, J.; Randall, S.; Xu, F.; Parker, H.; May, J.; Snowden, W. Emergence of resistance to protease inhibitor amprenavir in human immunodeficiency virus type 1-infected patients: selection of four alternative viral protease genotypes and influence of viral susceptibility to coadministered reverse transcriptase nucleoside inhibitors. Antimicrob. Agents Chemother.,  2002, 46(3), 731-738.
[http://dx.doi.org/10.1128/AAC.46.3.731-738.2002] [PMID:  11850255] 
[273] 
Marcelin, A.G.; Affolabi, D.; Lamotte, C.; Mohand, H.A.; Delaugerre, C.; Wirden, M.; Voujon, D.; Bossi, P.; Ktorza, N.; Bricaire, F.; Costagliola, D.; Katlama, C.; Peytavin, G.; Calvez, V. Resistance profiles observed in virological failures after 24 weeks of amprenavir/ritonavir containing regimen in protease inhibitor experienced patients. J. Med. Virol.,  2004, 74(1), 16-20.
[http://dx.doi.org/10.1002/jmv.20140] [PMID:  15258963] 
[274] 
Marcelin, A.G.; Flandre, P.; Molina, J.M.; Katlama, C.; Yeni, P.; Raffi, F.; Antoun, Z.; Ait-Khaled, M.; Calvez, V. Genotypic resistance analysis of the virological response to fosamprenavir-ritonavir in protease inhibitor-experienced patients in CONTEXT and TRIAD clinical trials. Antimicrob. Agents Chemother.,  2008, 52(12), 4251-4257.
[http://dx.doi.org/10.1128/AAC.00514-08] [PMID:  18852278] 
[275] 
Condra, J.H.; Holder, D.J.; Schleif, W.A.; Blahy, O.M.; Danovich, R.M.; Gabryelski, L.J.; Graham, D.J.; Laird, D.; Quintero, J.C.; Rhodes, A.; Robbins, H.L.; Roth, E.; Shivaprakash, M.; Yang, T.; Chodakewitz, J.A.; Deutsch, P.J.; Leavitt, R.Y.; Massari, F.E.; Mellors, J.W.; Squires, K.E.; Steigbigel, R.T.; Teppler, H.; Emini, E.A. Genetic correlates of in vivo viral resistance to indinavir, a human immunodeficiency virus type 1 protease inhibitor. J. Virol.,  1996, 70(12), 8270-8276.
[PMID:  8970946] 
[276] 
Bélec, L.; Piketty, C.; Si-Mohamed, A.; Goujon, C.; Hallouin, M.C.; Cotigny, S.; Weiss, L.; Kazatchkine, M.D. High levels of drug-resistant human immunodeficiency virus variants in patients exhibiting increasing CD4+ T cell counts despite virologic failure of protease inhibitor-containing antiretroviral combination therapy. J. Infect. Dis.,  2000, 181(5), 1808-1812.
[http://dx.doi.org/10.1086/315429] [PMID:  10823790] 
[277] 
Barber, T.J.; Harrison, L.; Asboe, D.; Williams, I.; Kirk, S.; Gilson, R.; Bansi, L.; Pillay, D.; Dunn, D.; Database, U.H.D.R.; Committees, U.K.C.H.C.S.S. Frequency and patterns of protease gene resistance mutations in HIV-infected patients treated with lopinavir/ritonavir as their first protease inhibitor. J. Antimicrob. Chemother.,  2012, 67(4), 995-1000.
[http://dx.doi.org/10.1093/jac/dkr569] [PMID:  22258921] 
[278] 
Mo, H.; King, M.S.; King, K.; Molla, A.; Brun, S.; Kempf, D.J. Selection of resistance in protease inhibitor-experienced, human immunodeficiency virus type 1-infected subjects failing lopinavir- and ritonavir-based therapy: Mutation patterns and baseline correlates. J. Virol.,  2005, 79(6), 3329-3338.
[http://dx.doi.org/10.1128/JVI.79.6.3329-3338.2005] [PMID:  15731227] 
[279] 
de Mendoza, C.; Valer, L.; Bacheler, L.; Pattery, T.; Corral, A.; Soriano, V. Prevalence of the HIV-1 protease mutation I47A in clinical practice and association with lopinavir resistance. AIDS,  2006, 20(7), 1071-1074.
[http://dx.doi.org/10.1097/01.aids.0000222084.44411.cc] [PMID:  16603864] 
[280] 
Rhee, S.Y.; Gonzales, M.J.; Kantor, R.; Betts, B.J.; Ravela, J.; Shafer, R.W. Human immunodeficiency virus reverse transcriptase and protease sequence database. Nucleic Acids Res.,  2003, 31(1), 298-303.
[http://dx.doi.org/10.1093/nar/gkg100] [PMID:  12520007] 
[281] 
Atkinson, B.; Isaacson, J.; Knowles, M.; Mazabel, E.; Patick, A.K. Correlation between human immunodeficiency virus genotypic resistance and virologic response in patients receiving nelfinavir monotherapy or nelfinavir with lamivudine and zidovudine. J. Infect. Dis.,  2000, 182(2), 420-427.
[http://dx.doi.org/10.1086/315726] [PMID:  10915071] 
[282] 
Patick, A.K.; Duran, M.; Cao, Y.; Shugarts, D.; Keller, M.R.; Mazabel, E.; Knowles, M.; Chapman, S.; Kuritzkes, D.R.; Markowitz, M. Genotypic and phenotypic characterization of human immunodeficiency virus type 1 variants isolated from patients treated with the protease inhibitor nelfinavir. Antimicrob. Agents Chemother.,  1998, 42(10), 2637-2644.
[http://dx.doi.org/10.1128/AAC.42.10.2637] [PMID:  9756769] 
[283] 
Mo, H.; Lu, L.; Dekhtyar, T.; Stewart, K.D.; Sun, E.; Kempf, D.J.; Molla, A. Characterization of resistant HIV variants generated by in vitro passage with lopinavir/ritonavir. Antiviral Res.,  2003, 59(3), 173-180.
[http://dx.doi.org/10.1016/S0166-3542(03)00107-4] [PMID:  12927307] 
[284] 
Kantor, R.; Fessel, W.J.; Zolopa, A.R.; Israelski, D.; Shulman, N.; Montoya, J.G.; Harbour, M.; Schapiro, J.M.; Shafer, R.W. Evolution of primary protease inhibitor resistance mutations during protease inhibitor salvage therapy. Antimicrob. Agents Chemother.,  2002, 46(4), 1086-1092.
[http://dx.doi.org/10.1128/AAC.46.4.1086-1092.2002] [PMID:  11897594] 
[285] 
Mitsuya, Y.; Winters, M.A.; Fessel, W.J.; Rhee, S.Y.; Hurley, L.; Horberg, M.; Schiffer, C.A.; Zolopa, A.R.; Shafer, R.W. N88D facilitates the co-occurrence of D30N and L90M and the development of multidrug resistance in HIV type 1 protease following nelfinavir treatment failure. AIDS Res. Hum. Retroviruses,  2006, 22(12), 1300-1305.
[http://dx.doi.org/10.1089/aid.2006.22.1300] [PMID:  17209774] 
[286] 
Baxter, J.D.; Schapiro, J.M.; Boucher, C.A.; Kohlbrenner, V.M.; Hall, D.B.; Scherer, J.R.; Mayers, D.L. Genotypic changes in human immunodeficiency virus type 1 protease associated with reduced susceptibility and virologic response to the protease inhibitor tipranavir. J. Virol.,  2006, 80(21), 10794-10801.
[http://dx.doi.org/10.1128/JVI.00712-06] [PMID:  16928764] 
[287] 
Schapiro, J.M.; Scherer, J.; Boucher, C.A.; Baxter, J.D.; Tilke, C.; Perno, C.F.; Maggiolo, F.; Santoro, M.M.; Hall, D.B. Improving the prediction of virological response to tipranavir: The development and validation of a tipranavir-weighted mutation score. Antivir. Ther. (Lond.),  2010, 15(7), 1011-1019.
[http://dx.doi.org/10.3851/IMP1670] [PMID:  21041916] 
[288] 
Rhee, S.Y.; Taylor, J.; Fessel, W.J.; Kaufman, D.; Towner, W.; Troia, P.; Ruane, P.; Hellinger, J.; Shirvani, V.; Zolopa, A.; Shafer, R.W. HIV-1 protease mutations and protease inhibitor cross-resistance. Antimicrob. Agents Chemother.,  2010, 54(10), 4253-4261.
[http://dx.doi.org/10.1128/AAC.00574-10] [PMID:  20660676] 
[289] 
Bethell, R.; Scherer, J.; Witvrouw, M.; Paquet, A.; Coakley, E.; Hall, D. Short communication: Phenotypic protease inhibitor resistance and cross-resistance in the clinic from 2006 to 2008 and mutational prevalences in HIV from patients with discordant tipranavir and darunavir susceptibility phenotypes. AIDS Res. Hum. Retroviruses,  2012, 28(9), 1019-1024.
[http://dx.doi.org/10.1089/aid.2011.0242] [PMID:  22098079] 
[290] 
Shahriar, R.; Rhee, S.Y.; Liu, T.F.; Fessel, W.J.; Scarsella, A.; Towner, W.; Holmes, S.P.; Zolopa, A.R.; Shafer, R.W. Nonpolymorphic human immunodeficiency virus type 1 protease and reverse transcriptase treatment-selected mutations. Antimicrob. Agents Chemother.,  2009, 53(11), 4869-4878.
[http://dx.doi.org/10.1128/AAC.00592-09] [PMID:  19721070] 
[291] 
Kim, R.; Baxter, J.D. Protease inhibitor resistance update: where are we now? AIDS Patient Care STDS,  2008, 22(4), 267-277.
[http://dx.doi.org/10.1089/apc.2007.0099] [PMID:  18422460] 
[292] 
Race, E.; Dam, E.; Obry, V.; Paulous, S.; Clavel, F. Analysis of HIV cross-resistance to protease inhibitors using a rapid single-cycle recombinant virus assay for patients failing on combination therapies. AIDS,  1999, 13(15), 2061-2068.
[http://dx.doi.org/10.1097/00002030-199910220-00008] [PMID:  10546858] 
[293] 
Doyon, L.; Croteau, G.; Thibeault, D.; Poulin, F.; Pilote, L.; Lamarre, D. Second locus involved in human immunodeficiency virus type 1 resistance to protease inhibitors. J. Virol.,  1996, 70(6), 3763-3769.
[PMID:  8648711] 
[294] 
Zhang, Y.M.; Imamichi, H.; Imamichi, T.; Lane, H.C.; Falloon, J.; Vasudevachari, M.B.; Salzman, N.P. Drug resistance during indinavir therapy is caused by mutations in the protease gene and in its Gag substrate cleavage sites. J. Virol.,  1997, 71(9), 6662-6670.
[PMID:  9261388] 
[295] 
Clavel, F.; Race, E.; Mammano, F. HIV drug resistance and viral fitness. Adv. Pharmacol.,  2000, 49, 41-66.
[http://dx.doi.org/10.1016/S1054-3589(00)49023-X] [PMID:  11013760] 
[296] 
Nijhuis, M.; Deeks, S.; Boucher, C. Implications of antiretroviral resistance on viral fitness. Curr. Opin. Infect. Dis.,  2001, 14(1), 23-28.
[http://dx.doi.org/10.1097/00001432-200102000-00005] [PMID:  11979111] 
[297] 
Miller, V. International perspectives on antiretroviral resistance. Resistance to protease inhibitors. J. Acquir. Immune Defic. Syndr.,  2001, 26(Suppl. 1), S34-S50.
[http://dx.doi.org/10.1097/00126334-200103011-00005] [PMID:  11265000] 
[298] 
Condra, J.H.; Schleif, W.A.; Blahy, O.M.; Gabryelski, L.J.; Graham, D.J.; Quintero, J.C.; Rhodes, A.; Robbins, H.L.; Roth, E.; Shivaprakash, M. In vivo emergence of HIV-1 variants resistant to multiple protease inhibitors. Nature,  1995, 374(6522), 569-571.
[http://dx.doi.org/10.1038/374569a0] [PMID:  7700387] 
[299] 
Molla, A.; Korneyeva, M.; Gao, Q.; Vasavanonda, S.; Schipper, P.J.; Mo, H.M.; Markowitz, M.; Chernyavskiy, T.; Niu, P.; Lyons, N.; Hsu, A.; Granneman, G.R.; Ho, D.D.; Boucher, C.A.; Leonard, J.M.; Norbeck, D.W.; Kempf, D.J. Ordered accumulation of mutations in HIV protease confers resistance to ritonavir. Nat. Med.,  1996, 2(7), 760-766.
[http://dx.doi.org/10.1038/nm0796-760] [PMID:  8673921] 
[300] 
Berkhout, B. HIV-1 evolution under pressure of protease inhibitors: climbing the stairs of viral fitness. J. Biomed. Sci.,  1999, 6(5), 298-305.
[http://dx.doi.org/10.1007/BF02253518] [PMID:  10494036] 
[301] 
Stolbach, A.; Paziana, K.; Heverling, H.; Pham, P. A Review of the toxicity of HIV medications II: Interactions with drugs and complementary and alternative medicine products. J. Med. Toxicol.,  2015, 11(3), 326-341.
[http://dx.doi.org/10.1007/s13181-015-0465-0] [PMID:  26036354] 
[302] 
Seden, K.; Back, D.; Khoo, S. Antiretroviral drug interactions: often unrecognized, frequently unavoidable, sometimes unmanageable. J. Antimicrob. Chemother.,  2009, 64(1), 5-8.
[http://dx.doi.org/10.1093/jac/dkp152] [PMID:  19398457] 
[303] 
Kurt Yilmaz, N.; Swanstrom, R.; Schiffer, C.A. Improving viral protease inhibitors to counter drug resistance. Trends Microbiol.,  2016, 24(7), 547-557.
[http://dx.doi.org/10.1016/j.tim.2016.03.010] [PMID:  27090931] 
[304] 
Weber, I.T.; Agniswamy, J. HIV-1 Protease: Structural Perspectives on Drug Resistance. Viruses,  2009, 1(3), 1110-1136.
[http://dx.doi.org/10.3390/v1031110] [PMID:  21994585] 
[305] 
Weber, I.T.; Kneller, D.W.; Wong-Sam, A. Highly resistant HIV-1 proteases and strategies for their inhibition. Future Med. Chem.,  2015, 7(8), 1023-1038.
[http://dx.doi.org/10.4155/fmc.15.44] [PMID:  26062399] 
[306] 
Ghosh, A.K.; Anderson, D.D.; Weber, I.T.; Mitsuya, H. Enhancing protein backbone binding-a fruitful concept for combating drug-resistant HIV. Angew. Chem. Int. Ed. Engl.,  2012, 51(8), 1778-1802.
[http://dx.doi.org/10.1002/anie.201102762] [PMID:  22290878] 
Rights & Permissions Print Cite
Article Metrics
70
11
Journal Information
For Authors
For Editors
For Reviewers
Explore Articles
Open Access
Open Access Articles
For Visitors
DOI https://dx.doi.org/10.2174/1568026619666190619115243	Print ISSN 1568-0266
Publisher Name Bentham Science Publisher	Online ISSN 1873-4294
Current Topics in Medicinal Chemistry

Protease Inhibitors for the Treatment of HIV/AIDS: Recent Advances and Future Challenges

Abstract Play Pause

Graphical Abstract

Related Journals

Related Books

Related Articles

Abstract
