Abstract
Bacterial infections have always been an unrestrained challenge to the medical community due to the rise of multi-drug tolerant and resistant strains. Pioneering work on Escherichia coli polyphosphate kinase (PPK) by Arthur Kornberg has generated great interest in this polyphosphate (PolyP) synthesizing enzyme. PPK has wide distribution among pathogens and is involved in promoting pathogenesis, stress management and susceptibility to antibiotics. Further, the absence of a PPK orthologue in humans makes it a potential drug target. This review covers the functional and structural aspects of polyphosphate kinases in bacterial pathogens. A description of molecules being designed against PPKs has been provided, challenges associated with PPK inhibitor design are highlighted and the strategies to enable development of efficient drug against this enzyme have also been discussed.
Keywords: Pathogenesis, virulence factors, stringent response, targeted inhibitor screening, PPK inhibitor, drug designing.
Graphical Abstract
[1]
Rice LB. Progress and challenges in implementing the research on ESKAPE pathogens. Infect Control Hosp Epidemiol 2010; 31(Suppl. 1): S7-S10.
[3]
Mathlouthi N, Al-Bayssari C, Bakour S, et al. Prevalence and emergence of carbapenemases-producing Gram-negative bacteria in Mediterranean basin. Crit Rev Microbiol 2016; 7828: 1-19.
[4]
Thaden JT, Pogue JM, Kaye KS. Role of newer and re-emerging older agents in the treatment of infections caused by carbapenem-resistant Enterobacteriaceae. Virulence 2016; 5594: 1-14.
[5]
Hirsch EB, Tam VH. Impact of multidrug-resistant Pseudomonas aeruginosa infection on patient outcomes. Expert Rev Pharmacoecon Outcomes Res 2010; 10: 441-51.
[7]
Fauvart M, de Groote VN, Michiels J. Role of persister cells in chronic infections: Clinical relevance and perspectives on anti-persister therapies. J Med Microbiol 2011; 60: 699-709.
[9]
Albi T, Serrano A. Inorganic polyphosphate in the microbial world. Emerging roles for a multifaceted biopolymer. World J Microbiol Biotechnol 2016; 32: 1-12.
[10]
Kulaev I, Vagabov V, Kulakovskaya T. New aspects of inorganic polyphosphate metabolism and function. J Biosci Bioeng 1999; 88: 111-29.
[11]
Pavlov E, Zakharian E, Bladen C, et al. A large, voltage-dependent channel, isolated from mitochondria by water-free chloroform extraction. Biophys J 2005; 88: 2614-25.
[12]
Wang L, Fraley CD, Faridi J, et al. Inorganic polyphosphate stimulates mammalian TOR, a kinase involved in the proliferation of mammary cancer cells. Proc Natl Acad Sci USA 2003; 100: 11249-54.
[14]
Morrissey JH, Choi SH, Smith SA. Polyphosphate: an ancient molecule that links platelets, coagulation, and inflammation. Blood 2012; 119: 5972-9.
[15]
Pavlov E, Aschar-Sobbi R, Campanella M, et al. Inorganic polyphosphate and energy metabolism in mammalian cells. J Biol Chem 2010; 285: 9420-8.
[16]
Brown MRW, Kornberg A. Inorganic polyphosphate in the origin and survival of species. Proc Natl Acad Sci USA 2004; 101: 16085-7.
[17]
Tzeng CM, Kornberg A. The multiple activities of polyphosphate kinase of Escherichia coli and their subunit structure determined by radiation target analysis. J Biol Chem 2000; 275: 3977-83.
[18]
Kornberg SR. Adenosine triphosphate synthesis from polyphosphate by an enzyme from Escherichia coli. Biochim Biophys Acta 1957; 26: 294-300.
[19]
Achbergerová L, Nahálka J. Polyphosphate - an ancient energy source and active metabolic regulator. Microb Cell Fact 2011; 10: 63.
[20]
Ahn K, Kornberg A. Polyphosphate kinase from Escherichia coli. Purification and demonstration of a phosphoenzyme intermediate. J Biol Chem 1990; 265: 11734-9.
[21]
Akiyama M, Crooke E, Kornberg A. The polyphosphate kinase gene of Escherichia coli. Isolation and sequence of the ppk gene and membrane location of the protein. J Biol Chem 1992; 267: 22556-61.
[22]
Zhang H, Gómez-García MR, Shi X, et al. Polyphosphate kinase 1, a conserved bacterial enzyme, in a eukaryote, Dictyostelium discoideum, with a role in cytokinesis. Proc Natl Acad Sci USA 2007; 104: 16486-91.
[23]
Zhu Y, Huang W, Lee SSK, et al. Crystal structure of a polyphosphate kinase and its implications for polyphosphate synthesis. EMBO Rep 2005; 6: 681-7.
[24]
Esnault C, Leiber D, Toffano-Nioche C, et al. Another example of enzymatic promiscuity: the polyphosphate kinase of Streptomyces lividans is endowed with phospholipase D activity. Appl Microbiol Biotechnol 2017; 101(1): 139-45.
[25]
Tinsley CR, Gotschlich EC. Cloning and characterization of the meningococcal polyphosphate kinase gene: Production of polyphosphate synthesis mutants. Infect Immun 1995; 63: 1624-30.
[26]
Cole ST, Brosch R, Parkhill J, et al. Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature 1998; 393: 537-44.
[27]
Zhang H, Ishige K, Kornberg A. A polyphosphate kinase (PPK2) widely conserved in bacteria. Proc Natl Acad Sci USA 2002; 99: 16678-83.
[28]
Itoh H, Shiba T. Polyphosphate synthetic activity of polyphosphate: AMP phosphotransferase in Acinetobacter johnsonii 210A. J Bacteriol 2004; 186: 5178-81.
[29]
Motomura K, Hirota R, Okada M, et al. A new subfamily of polyphosphate kinase 2 (Class III PPK2) catalyzes both nucleoside monophosphate phosphorylation and nucleoside diphosphate phosphorylation. Appl Environ Microbiol 2014; 80: 2602-8.
[30]
Fioravanti E, Haouz A, Ursby T, et al. Mycobacterium tuberculosis thymidylate kinase: Structural studies of intermediates along the reaction pathway. J Mol Biol 2003; 327: 1077-92.
[31]
Nocek B, Kochinyan S, Proudfoot M, et al. Polyphosphate-dependent synthesis of ATP and ADP by the family-2 polyphosphate kinases in bacteria. Proc Natl Acad Sci USA 2008; 105: 17730-5.
[32]
García Martín H, Ivanova N, Kunin V, et al. Metagenomic analysis of two enhanced biological phosphorus removal (EBPR) sludge communities. Nat Biotechnol 2006; 24: 1263-9.
[33]
Ishige K, Zhang H, Kornberg A. Polyphosphate kinase (PPK2), a potent, polyphosphate-driven generator of GTP. Proc Natl Acad Sci USA 2002; 99: 16684-8.
[34]
Shiba T, Itoh H, Kameda A, et al. Polyphosphate:AMP phosphotransferase as a polyphosphate-dependent nucleoside monophosphate kinase in Acinetobacter johnsonii 210A. J Bacteriol 2005; 187: 1859-65.
[35]
Akiyama M, Crooke E, Kornberg A. An exopolyphosphatase of Escherichia coli: The enzyme and its ppx gene in a polyphosphate operon. J Biol Chem 1993; 268: 633-9.
[36]
Thayil SM, Morrison N, Schechter N, et al. The role of the novel exopolyphosphatase MT0516 in Mycobacterium tuberculosis drug tolerance and persistence. PLoS One 2011; 6: e28076.
[37]
Zhang A, Guo E, Qian L, et al. Purification, crystallization and X-ray crystallographic analysis of a putative exopolyphosphatase from Zymomonas mobilis. Acta Crystallogr Sect F. Struct Biol Commun 2016; 72: 172-8.
[38]
Kornberg A, Rao NN, Ault-Riché D. Inorganic polyphosphate: A molecule of many functions. Annu Rev Biochem 1999; 68: 89-125.
[39]
Shum KT, Lui ELH, Wong SCK, et al. Aptamer-mediated inhibition of Mycobacterium tuberculosis polyphosphate kinase 2. Biochemistry 2011; 50: 3261-71.
[40]
Parnell AE, Mordhorst S, Kemper F, et al. Substrate recognition and mechanism revealed by ligand-bound polyphosphate kinase 2 structures. Proc Natl Acad Sci 2018; 115: 3350-5.
[41]
Cui Q, Shin WS, Luo Y, et al. Thymidylate kinase: an old topic brings new perspectives. Curr Med Chem 2013; 20: 1286-305.
[42]
Sureka K, Sanyal S, Basu J, et al. Polyphosphate kinase 2: A modulator of nucleoside diphosphate kinase activity in mycobacteria. Mol Microbiol 2009; 74: 1187-97.
[43]
Nocek B, Hatzos-Skintges C, Feldmann B, et al. Crystal structure of Polyphosphate Kinase 2 from Arthrobacter aurescens TC1. to be Publ. DOI: 10.2210/pdb3rhf/pdb
[44]
Batten LE, Parnell AE, Wells NJ, et al. Biochemical and structural characterization of polyphosphate kinase 2 from the intracellular pathogen Francisella tularensis. Biosci Rep 2016; 36: e00294-4.
[45]
Beceiro A, Tomás M, Bou G. Antimicrobial resistance and virulence: a successful or deleterious association in the bacterial world? Clin Microbiol Rev 2013; 26: 185-230.
[46]
Rijavec M, Muller-Premru M, Zakotnik B, et al. Virulence factors and biofilm production among Escherichia coli strains causing bacteraemia of urinary tract origin. J Med Microbiol 2008; 57: 1329-34.
[47]
Mongkolrob R, Taweechaisupapong S, Tungpradabkul S. Correlation between biofilm production, antibiotic susceptibility and exopolysaccharide composition in Burkholderia pseudomallei bps I, ppk, and rpo S mutant strains. Microbiol Immunol 2015; 59: 653-63.
[48]
Colvin KM, Irie Y, Tart CS, et al. The Pel and Psl polysaccharides provide Pseudomonas aeruginosa structural redundancy within the biofilm matrix. Environ Microbiol 2012; 14: 1913-28.
[49]
Rashid MH, Rumbaugh K, Passador L, et al. Polyphosphate kinase is essential for biofilm development, quorum sensing, and virulence of Pseudomonas aeruginosa. Proc Natl Acad Sci USA 2000; 97: 9636-41.
[50]
Chen W, Palmer RJ, Kuramitsu HK. Role of polyphosphate kinase in biofilm formation by Porphyromonas gingivalis. Infect Immun 2002; 70: 4708-15.
[51]
Shi X, Rao NN, Kornberg A. Inorganic polyphosphate in Bacillus cereus: motility, biofilm formation, and sporulation. Proc Natl Acad Sci USA 2004; 101: 17061-5.
[52]
Grillo-Puertas M, Villegas JM, Rintoul MR, et al. Polyphosphate degradation in stationary phase triggers biofilm formation via luxs quorum sensing system in escherichia coli. PLoS One 2012; 7: e50368.
[53]
Sundin GW, Shankar S, Chugani SA, et al. Nucleoside diphosphate kinase from Pseudomonas aeruginosa: Characterization of the gene and its role in cellular growth and exopolysaccharide alginate synthesis. Mol Microbiol 1996; 20: 965-79.
[54]
Kamath S, Kapatral V, Chakrabarty AM. Cellular function of elastase in Pseudomonas aeruginosa: Role in the cleavage of nucleoside diphosphate kinase and in alginate synthesis. Mol Microbiol 1998; 30: 933-41.
[55]
Pier GB, Coleman F, Grout M, et al. Role of alginate O acetylation in resistance of mucoid Pseudomonas aeruginosa to opsonic phagocytosis. Infect Immun 2001; 69: 1895-901.
[56]
Chakrabarty AM. Nucleoside diphosphate kinase: role in bacterial growth, virulence, cell signalling and polysaccharide synthesis. Mol Microbiol 1998; 28: 875-82.
[57]
Leid JG, Willson CJ, Shirtliff ME, et al. The exopolysaccharide alginate protects Pseudomonas aeruginosa biofilm bacteria from IFN-gamma-mediated macrophage killing. J Immunol 2005; 175: 7512-8.
[58]
Chuang Y-MM, Dutta NK, Hung C-FF, et al. Stringent response factors PPX1 and PPK2 play an important role in Mycobacterium tuberculosis metabolism, biofilm formation, and sensitivity to isoniazid In Vivo. Antimicrob Agents Chemother 2016; 60: 6460-70.
[59]
Chuang YM, Bandyopadhyay N, Rifat D, et al. Deficiency of the novel exopolyphosphatase Rv1026/PPX2 leads to metabolic downshift and altered cell wall permeability in Mycobacterium tuberculosis. MBio 2015; 6: e02428-14.
[60]
Kim K-S, Rao NN, Fraley CD, et al. Inorganic polyphosphate is essential for long-term survival and virulence factors in Shigella and Salmonella spp. Proc Natl Acad Sci USA 2002; 99: 7675-80.
[61]
Ayraud S, Janvier B, Salaun L, et al. Modification in the ppk gene of Helicobacter pylori during single and multiple experimental murine infections. Infect Immun 2003; 71: 1733-9.
[62]
Tan S, Fraley CD, Zhang M, et al. Diverse phenotypes resulting from polyphosphate kinase gene (ppk1) inactivation in different strains of Helicobacter pylori. J Bacteriol 2005; 187: 7687-95.
[63]
Peng L, Luo W-Y, Zhao T, et al. Polyphosphate kinase 1 is required for the pathogenesis process of meningitic Escherichia coli K1 (RS218). Future Microbiol 2012; 7: 411-23.
[64]
Singh M, Tiwari P, Arora G, et al. Establishing Virulence Associated Polyphosphate Kinase 2 as a drug target for Mycobacterium tuberculosis. Sci Rep 2016; 6: 26900.
[65]
Kuroda A. Degradation by the lon protease in E. coli role of inorganic polyphosphate in promoting ribosomal protein degradation by the lon protease in E. coli. Sci 2011; 705: 705-8.
[66]
Nomura K, Kato J, Takiguchi N, et al. Effects of inorganic polyphosphate on the proteolytic and DNA-binding activities of lon in Escherichia coli. J Biol Chem 2004; 279: 34406-10.
[67]
Shiba T, Tsutsumi K, Yano H, et al. Inorganic polyphosphate and the induction of rpoS expression. Proc Natl Acad Sci USA 1997; 94: 11210-5.
[68]
Shiba T, Tsutsumi K, Ishige K, et al. Inorganic polyphosphate and polyphosphate kinase: Their novel biological functions and applications. Biochem Biokhimii͡a 2000; 65: 315-23.
[69]
Tunpiboonsak S, Mongkolrob R, Kitudomsub K, et al. Role of a Burkholderia pseudomallei polyphosphate kinase in an oxidative stress response, motilities, and biofilm formation. J Microbiol 2010; 48: 63-70.
[70]
Gray M, Wholey WY, Wagner N, et al. Polyphosphate Is a Primordial Chaperone. Mol Cell 2014; 53: 689-99.
[71]
Gray MJ, Jakob U. Oxidative stress protection by polyphosphate--new roles for an old player. Curr Opin Microbiol 2015; 24: 1-6.
[72]
Candon HL, Allan BJ, Fraley CD, et al. Polyphosphate kinase 1 is a pathogenesis determinant in Campylobacter jejuni. J Bacteriol 2007; 189: 8099-108.
[73]
Candon HL, Allan BJ, Fraley CD, et al. Polyphosphate kinase 1 is a pathogenesis determinant in Campylobacter jejuni. J Bacteriol 2007; 189: 8099-108.
[74]
Gangaiah D, Kassem II, Liu Z, et al. Importance of polyphosphate kinase 1 for Campylobacter jejuni viable-but-nonculturable cell formation, natural transformation, and antimicrobial resistance. Appl Environ Microbiol 2009; 75: 7838-49.
[75]
Pina-Mimbela R, Madrid JA, Kumar A, et al. Polyphosphate kinases modulate Campylobacter jejuni outer membrane constituents and alter its capacity to invade and survive in intestinal epithelial cells in vitro. Emerg Microbes Infect 2015; 4: e77.
[76]
Peng L, Jiang Q, Pan JY, et al. Involvement of polyphosphate kinase in virulence and stress tolerance of uropathogenic Proteus mirabilis. Med Microbiol Immunol 2016; 205: 97-109.
[77]
Ortiz-Severín J, Varas M, Bravo-Toncio C, et al. Multiple antibiotic susceptibility of polyphosphate kinase mutants (ppk1 and ppk2) from Pseudomonas aeruginosa PAO1 as revealed by global phenotypic analysis. Biol Res 2015; 48: 22.
[78]
Chen J, Su L, Wang X, et al. Polyphosphate kinase mediates antibiotic tolerance in extraintestinal pathogenic Escherichia coli PCN033. Front Microbiol 2016; 7: 724.
[79]
Richards MI, Michell SL, Oyston PCF. An intracellularly inducible gene involved in virulence and polyphosphate production in Francisella. J Med Microbiol 2008; 57: 1183-92.
[80]
Rao NN, Kornberg A. Inorganic polyphosphate supports resistance and survival of stationary-phase Escherichia coli. J Bacteriol 1996; 178: 1394-400.
[81]
Varas M, Valdivieso C, Mauriaca C, et al. Multi-level evaluation of Escherichia coli polyphosphate related mutants using global transcriptomic, proteomic and phenomic analyses. Biochim Biophys Acta, Gen Subj 2017; 1861: 871-83.
[82]
Ayraud S, Janvier B, Labigne A, et al. Polyphosphate kinase: A new colonization factor of Helicobacter pylori. FEMS Microbiol Lett 2005; 243: 45-50.
[83]
Singh R, Singh M, Arora G, et al. Polyphosphate deficiency in Mycobacterium tuberculosis is associated with enhanced drug susceptibility and impaired growth in guinea pigs. J Bacteriol 2013; 195: 2839-51.
[84]
Chuang YM, Belchis DA, Karakousis PC. The polyphosphate kinase gene ppk2 is required for Mycobacterium tuberculosis inorganic polyphosphate regulation and virulence. MBio 2013; 4: e00039-13.
[85]
Fraley CD, Rashid MH, Lee SSK, et al. A polyphosphate kinase 1 (ppk1) mutant of Pseudomonas aeruginosa exhibits multiple ultrastructural and functional defects. Proc Natl Acad Sci 2007; 104: 3526-31.
[86]
Racki LR, Tocheva EI, Dieterle MG, et al. Polyphosphate granule biogenesis is temporally and functionally tied to cell cycle exit during starvation in Pseudomonas aeruginosa. Proc Natl Acad Sci 2017; 114: E2440-9.
[87]
Jagannathan V, Kaur P, Datta S. Polyphosphate kinase from m. tuberculosis: An interconnect between the genetic and biochemical role. PLoS One 2010; 5: e14336.
[88]
Makino K, Shinagawa H, Amemura M, et al. Signal transduction in the phosphate regulon of Escherichia coli involves phosphotransfer between PhoR and PhoB proteins. J Mol Biol 1989; 210: 551-9.
[89]
Shi L, Liu W, Hulett FM. Decay of activated Bacillus subtilis Pho response regulator, PhoP~P, involves the PhoR~P intermediate. Biochemistry 1999; 38: 10119-25.
[90]
Shi L, Hulett FM. The cytoplasmic kinase domain of PhoR is sufficient for the low phosphate-inducible expression of Pho regulon genes in Bacillus subtilis. Mol Microbiol 1999; 31: 211-22.
[91]
Peng YC, Lu CY, Li G, et al. Induction of the pho regulon and polyphosphate synthesis against spermine stress in Pseudomonas aeruginosa. Mol Microbiol 2017; 104: 1037-51.
[92]
Crépin S, Chekabab SM, Le Bihan G, et al. The Pho regulon and the pathogenesis of Escherichia coli. Vet Microbiol 2011; 153: 82-8.
[93]
Rice CD, Pollard JE, Lewis ZT, et al. Employment of a promoter-swapping technique shows that PhoU modulates the activity of the PstSCAB2 ABC transporter in Escherichia coli. Appl Environ Microbiol 2009; 75: 573-82.
[94]
Prágai Z, Allenby NEE, O’Connor N, et al. Transcriptional regulation of the phoPR operon in Bacillus subtilis. In: Journal of Bacteriology. American Society for Microbiology 2004; pp. 1182-90.
[95]
Santos-Beneit F. The Pho regulon: A huge regulatory network in bacteria. Front Microbiol 2015; 6: 402.
[96]
Carmany DO, Hollingsworth K, McCleary WR. Genetic and biochemical studies of phosphatase activity of PhoR. J Bacteriol 2003; 185: 1112-5.
[97]
Kato J, Yamamoto T, Yamada K, et al. Cloning, sequence and characterization of the polyphosphate kinase-encoding gene (ppk) of Klebsiella aerogenes. Gene 1993; 137: 237-42.
[98]
Ghorbel S, Smirnov A, Chouayekh H, et al. Regulation of ppk Expression and In Vivo Function of Ppk in Streptomyces lividans TK24. J Bacteriol 2006; 188: 6269-76.
[99]
Smirnov A, Esnault C, Prigent M, et al. Phosphate homeostasis in conditions of phosphate proficiency and limitation in the wild type and the phoP mutant of Streptomyces lividans. PLoS One 2015; 10: e0126221.
[100]
Tsutsumi K, Munekata M, Shiba T. Involvement of inorganic polyphosphate in expression of SOS genesBiochim Biophys Acta - Gene Struct Expr 2000; 1493: 73-81
[101]
Booth I. Escherichia coli and Salmonella typhimurium; Cellular and Molecular Biology, Vol. 1 (of2). Trends Biochem Sci 1988; 13: 493-4.
[102]
Kuroda A, Murphy H, Cashel M, et al. Guanosine tetra- and pentaphosphate promote accumulation of inorganic polyphosphate in Escherichia coli. J Biol Chem 1997; 272: 21240-3.
[103]
Sanyal S, Banerjee SK, Banerjee R, et al. Polyphosphate kinase 1, a central node in the stress response network of Mycobacterium tuberculosis, connects the two-component systems MprAB and SenX3-RegX3 and the extracytoplasmic function sigma factor, sigma E. Microbiol (United Kingdom) 2013; 159: 2074-86.
[104]
Rifat D, Bishai WR, Karakousis PC. Phosphate depletion: a novel trigger for Mycobacterium tuberculosis persistence. J Infect Dis 2009; 200: 1126-35.
[105]
Glover RT, Kriakov J, Garforth SJ, et al. The two-component regulatory system senX3-regX3 regulates phosphate-dependent gene expression in Mycobacterium smegmatis. J Bacteriol 2007; 189: 5495-503.
[106]
Sureka K, Dey S, Datta P, et al. Polyphosphate kinase is involved in stress-induced mprAB-sigE-rel signalling in mycobacteria. Mol Microbiol 2007; 65: 261-76.
[107]
He H, Hovey R, Kane J, et al. MprAB is a stress-responsive two-component system that directly regulates expression of sigma factors SigB and SigE in Mycobacterium tuberculosis. J Bacteriol 2006; 188: 2134-43.
[109]
Ault-Riche D, Kornberg A. Definitive enzymatic assays in polyphosphate analysis. Prog Mol Subcell Biol 1999; 23: 241-52.
[111]
Trager RE, Giblock P, Soltani S, et al. Docking optimization, variance and promiscuity for large-scale drug-like chemical space using high performance computing architectures. Drug Discov Today 2016; 21: 1672-80.
[112]
Chavez FP, Lagos CF, Reyes-Parada M, et al. Polyphosphate synthesis as a target for novel antibiotics. Curr Enzym Inhib 2011; 7: 163-8.
[113]
Saha SB, Verma V. in Silico analysis of Escherichia coli polyphosphate kinase (PPK) as a novel antimicrobial drug target and its high throughput virtual screening against PubChem library. Bioinformation 2013; 9: 518-23.
[114]
Tuttle T, Kraka E, Cremer D. Docking, triggering, and biological activity of dynemicin A in DNA: A computational study. J Am Chem Soc 2005; 127: 9469-84.
[115]
Vittimberga BM. The muconomycins. I. studies on the structure of muconomycin A, a new biologically active compound 1. J Org Chem 1963; 28: 1786-9.
[116]
Engelhorn ME, Guevara-Patiño JA, Merghoub T, et al. Mechanisms of immunization against cancer using chimeric antigens. Mol Ther 2008; 16: 773-81.
[117]
Hande KR. Etoposide: Four decades of development of a topoisomerase II inhibitor. Eur J Cancer 1998; 34: 1514-21.
[118]
Babé LM, Rosé J, Craik CS, et al. Trans-dominant inhibitory human immunodeficiency virus type 1 protease monomers prevent protease activation and virion maturation. Proc Natl Acad Sci USA 1995; 92: 10069-73.
[119]
Cardinale D, Salo-Ahen OMH, Ferrari S, et al. Homodimeric enzymes as drug targets. Curr Med Chem 2010; 17: 826-46.
[120]
Tintori C, Demeulemeester J, Franchi L, et al. Discovery of small molecule HIV-1 integrase dimerization inhibitors. Bioorg Med Chem Lett 2012; 22: 3109-14.
[121]
Newman D. Screening and identification of novel biologically active natural compounds. F1000 Res 2017; 6: 783.
[122]
Rollinger JM, Stuppner H, Langer T. Virtual screening for the discovery of bioactive natural products. Prog Drug Res 2008; 65: 212-49.
[123]
Shum K-T, Zhou J, Rossi JJ. Aptamer-based therapeutics: new approaches to combat human viral diseases. Pharmaceuticals (Basel) 2013; 6: 1507-42.
Article Metrics
71
15