Abstract
Dengue fever is a disease which is caused by a family of viruses named Flaviviridae which are transmitted by female Aedes mosquitoes. Today, this is endemic in more than 100 nations in the World Health Organization's African, Americas, Eastern Mediterranean, South-East Asia and Western Pacific locales. The treatment of typical dengue is focused on relieving the symptoms and signs. Carica papaya is a very common plant whose leaf extract is used in the treatment of this disease. Despite extensive research on Dengue, not a single vaccine or anti-viral drug was available until 2016 (a partially effective Chimeric Yellow fever virus treated by DENV-Tetravalent Dengue Vaccine for dengue fever made by Sanofi Pasteur). This review highlights dengue fever’s current situation and explains the importance of Natural chemical moieties like methionine–proline anilides, tetrapeptide aldehyde uncovered via Structure Activity Relationship studies. Also, we have reviewed the drug candidates currently in the clinical trials that have the potential to solve these issues. Important patents in the past 20 years have been outlined in this review. An in depth Protein Data Bank analysis of the different possible target proteins that can potentially have a major role in curing Dengue fever has been conducted.
Keywords: Dengue transmission, structural proteins, non structural proteins, protein data bank, in silico work, clinical studies, patent.
Graphical Abstract
[1]
Guzman MG, Halstead SB, Artsob H, et al. Dengue: a continuing global threat. Nat Rev Microbiol 2010; 8(12)(Suppl.): S7-S16.
[http://dx.doi.org/10.1038/nrmicro2460] [PMID: 21079655]
[http://dx.doi.org/10.1038/nrmicro2460] [PMID: 21079655]
[2]
Heilman JM, De Wolff J, Beards GM, Basden BJ. Dengue fever: a Wikipedia clinical review. Open Med 2014; 8(4): e105-15.
[PMID: 25426178]
[PMID: 25426178]
[3]
Gubler DJ. Dengue and dengue hemorrhagic fever. Clin Microbiol Rev 1998; 11(3): 480-96.
[http://dx.doi.org/10.1128/CMR.11.3.480] [PMID: 9665979]
[http://dx.doi.org/10.1128/CMR.11.3.480] [PMID: 9665979]
[5]
Ahmad N, Fazal H, Ayaz M, Abbasi BH, Mohammad I, Fazal L. Dengue fever treatment with Carica papaya leaves extracts. Asian Pac J Trop Biomed 2011; 1(4): 330-3.
[http://dx.doi.org/10.1016/S2221-1691(11)60055-5] [PMID: 23569787]
[http://dx.doi.org/10.1016/S2221-1691(11)60055-5] [PMID: 23569787]
[8]
Gupta E, Ballani N. Current perspectives on the spread of dengue in India. Infect Drug Resist 2014; 7: 337-42.
[http://dx.doi.org/10.2147/IDR.S55376] [PMID: 25525374]
[http://dx.doi.org/10.2147/IDR.S55376] [PMID: 25525374]
[9]
Fusco D, Chung R. Review of current dengue treatment and therapeutics in development. J Bioanal Biomed 2014; (8): 1.
[10]
Low JG, Ooi EE, Vasudevan SG. Current status of dengue therapeutics research and development. J Infect Dis 2017; (2): S96-S102. (8)
[11]
Hitesh A. Solanki, Shetty Shilpa Shankar, Himanshu A. Pandya. Dengue as a druggable disease: A review. J Fever 2017; 1(1): 1001.
[12]
Cockburn JJ, Navarro Sanchez ME, Fretes N, et al. Mechanism of dengue virus broad cross-neutralization by a monoclonal antibody. Structure 2012; 20(2): 303-14.
[http://dx.doi.org/10.1016/j.str.2012.01.001] [PMID: 22285214]
[http://dx.doi.org/10.1016/j.str.2012.01.001] [PMID: 22285214]
[13]
Midgley CM, Flanagan A, Tran HB, et al. Structural analysis of a dengue cross-reactive antibody complexed with envelope domain III reveals the molecular basis of cross-reactivity. J Immunol 2012; 188(10): 4971-9.
[http://dx.doi.org/10.4049/jimmunol.1200227] [PMID: 22491255]
[http://dx.doi.org/10.4049/jimmunol.1200227] [PMID: 22491255]
[14]
Elahi M, Islam MM, Noguchi K, Yohda M, Kuroda Y. High resolution crystal structure of dengue-3 envelope protein domain III suggests possible molecular mechanisms for serospecific antibody recognition. Proteins 2013; 81(6): 1090-5.
[http://dx.doi.org/10.1002/prot.24237] [PMID: 23239402]
[http://dx.doi.org/10.1002/prot.24237] [PMID: 23239402]
[15]
Klein DE, Choi JL, Harrison SC. Structure of a dengue virus envelope protein late-stage fusion intermediate. J Virol 2013; 87(4): 2287-93.
[http://dx.doi.org/10.1128/JVI.02957-12] [PMID: 23236058]
[http://dx.doi.org/10.1128/JVI.02957-12] [PMID: 23236058]
[16]
Modis Y, Ogata S, Clements D, Harrison SC. Structure of the dengue virus envelope protein after membrane fusion. Nature 2004; 427(6972): 313-9.
[http://dx.doi.org/10.1038/nature02165] [PMID: 14737159]
[http://dx.doi.org/10.1038/nature02165] [PMID: 14737159]
[17]
Kulkarni MR, Numoto N, Ito N, Kuroda Y. Modeling and experimental assessment of a buried Leu-Ile mutation in dengue envelope domain III. Biochem Biophys Res Commun 2016; 471(1): 163-8.
[http://dx.doi.org/10.1016/j.bbrc.2016.01.159] [PMID: 26826384]
[http://dx.doi.org/10.1016/j.bbrc.2016.01.159] [PMID: 26826384]
[18]
Li L, Lok S-M, Yu I-M, et al. The flavivirus precursor membrane-envelope protein complex: structure and maturation. Science 2008; 319(5871): 1830-4.
[http://dx.doi.org/10.1126/science.1153263] [PMID: 18369147]
[http://dx.doi.org/10.1126/science.1153263] [PMID: 18369147]
[19]
Edeling MA, Diamond MS, Fremont DH. Structural basis of Flavivirus NS1 assembly and antibody recognition. Proc Natl Acad Sci USA 2014; 111(11): 4285-90.
[http://dx.doi.org/10.1073/pnas.1322036111] [PMID: 24594604]
[http://dx.doi.org/10.1073/pnas.1322036111] [PMID: 24594604]
[20]
Akey DL, Brown WC, Dutta S, et al. Flavivirus NS1 structures reveal surfaces for associations with membranes and the immune system. Science 2014; 343(6173): 881-5.
[http://dx.doi.org/10.1126/science.1247749] [PMID: 24505133]
[http://dx.doi.org/10.1126/science.1247749] [PMID: 24505133]
[21]
Erbel P, Schiering N, D’Arcy A, et al. Structural basis for the activation of flaviviral NS3 proteases from dengue and West Nile virus. Nat Struct Mol Biol 2006; 13(4): 372-3.
[http://dx.doi.org/10.1038/nsmb1073] [PMID: 16532006]
[http://dx.doi.org/10.1038/nsmb1073] [PMID: 16532006]
[22]
Chandramouli S, Joseph JS, Daudenarde S, Gatchalian J, Cornillez-Ty C, Kuhn P. Serotype-specific structural differences in the protease-cofactor complexes of the dengue virus family. J Virol 2010; 84(6): 3059-67.
[http://dx.doi.org/10.1128/JVI.02044-09] [PMID: 20042502]
[http://dx.doi.org/10.1128/JVI.02044-09] [PMID: 20042502]
[23]
Luo D, Xu T, Watson RP, et al. Insights into RNA unwinding and ATP hydrolysis by the flavivirus NS3 protein. EMBO J 2008; 27(23): 3209-19.
[http://dx.doi.org/10.1038/emboj.2008.232] [PMID: 19008861]
[http://dx.doi.org/10.1038/emboj.2008.232] [PMID: 19008861]
[24]
Benmansour F, Trist I, Coutard B, et al. Discovery of novel dengue virus NS5 methyltransferase non-nucleoside inhibitors by fragment-based drug design. Eur J Med Chem 2017; 125: 865-80.
[http://dx.doi.org/10.1016/j.ejmech.2016.10.007] [PMID: 27750202]
[http://dx.doi.org/10.1016/j.ejmech.2016.10.007] [PMID: 27750202]
[25]
Coutard B, Decroly E, Li C, et al. Assessment of Dengue virus helicase and methyltransferase as targets for fragment-based drug discovery. Antiviral Res 2014; 106: 61-70.
[http://dx.doi.org/10.1016/j.antiviral.2014.03.013] [PMID: 24704437]
[http://dx.doi.org/10.1016/j.antiviral.2014.03.013] [PMID: 24704437]
[26]
Noble CG, Li S-H, Dong H, Chew SH, Shi PY. Crystal structure of dengue virus methyltransferase without S-adenosyl-L-methionine. Antiviral Res 2014; 111: 78-81.
[http://dx.doi.org/10.1016/j.antiviral.2014.09.003] [PMID: 25241250]
[http://dx.doi.org/10.1016/j.antiviral.2014.09.003] [PMID: 25241250]
[27]
Lim SP, Sonntag LS, Noble C, et al. Small molecule inhibitors that selectively block dengue virus methyltransferase. J Biol Chem 2011; 286(8): 6233-40.
[http://dx.doi.org/10.1074/jbc.M110.179184] [PMID: 21147775]
[http://dx.doi.org/10.1074/jbc.M110.179184] [PMID: 21147775]
[28]
Noble CG, Lim SP, Chen Y-L, et al. Conformational flexibility of the Dengue virus RNA-dependent RNA polymerase revealed by a complex with an inhibitor. J Virol 2013; 87(9): 5291-5.
[http://dx.doi.org/10.1128/JVI.00045-13] [PMID: 23408636]
[http://dx.doi.org/10.1128/JVI.00045-13] [PMID: 23408636]
[29]
Egloff M-P, Decroly E, Malet H, et al. Structural and functional analysis of methylation and 5′-RNA sequence requirements of short capped RNAs by the methyltransferase domain of dengue virus NS5. J Mol Biol 2007; 372(3): 723-36.
[http://dx.doi.org/10.1016/j.jmb.2007.07.005] [PMID: 17686489]
[http://dx.doi.org/10.1016/j.jmb.2007.07.005] [PMID: 17686489]
[30]
Yap TL, Xu T, Chen Y-L, et al. Crystal structure of the dengue virus RNA-dependent RNA polymerase catalytic domain at 1.85-angstrom resolution. J Virol 2007; 81(9): 4753-65.
[http://dx.doi.org/10.1128/JVI.02283-06] [PMID: 17301146]
[http://dx.doi.org/10.1128/JVI.02283-06] [PMID: 17301146]
[31]
Ma L, Jones CT, Groesch TD, Kuhn RJ, Post CB. Solution structure of dengue virus capsid protein reveals another fold. Proc Natl Acad Sci USA 2004; 101(10): 3414-9.
[http://dx.doi.org/10.1073/pnas.0305892101] [PMID: 14993605]
[http://dx.doi.org/10.1073/pnas.0305892101] [PMID: 14993605]
[32]
Xie X, Gayen S, Kang C, Yuan Z, Shi PY. Membrane topology and function of dengue virus NS2A protein. J Virol 2013; 87(8): 4609-22.
[http://dx.doi.org/10.1128/JVI.02424-12] [PMID: 23408612]
[http://dx.doi.org/10.1128/JVI.02424-12] [PMID: 23408612]
[33]
Bhatt S, Gething PW, Brady OJ, et al. The global distribution and burden of dengue. Nature 2013; 496(7446): 504-7.
[http://dx.doi.org/10.1038/nature12060] [PMID: 23563266]
[http://dx.doi.org/10.1038/nature12060] [PMID: 23563266]
[34]
Brady OJ, Gething PW, Bhatt S, et al. Refining the global spatial limits of dengue virus transmission by evidence-based consensus. PLoS Negl Trop Dis 2012; 6(8)e1760
[http://dx.doi.org/10.1371/journal.pntd.0001760] [PMID: 22880140]
[http://dx.doi.org/10.1371/journal.pntd.0001760] [PMID: 22880140]
[36]
Distribution of Dengue worldwide. 2016.http://www.who.int/denguecontrol/epidemiology/Average_number_suspected_confirmed_dengue_cases_reported_2010_2016_1450px.jpg?ua=1
[37]
Dengue Cases and Deaths in the Country since. 2015.nvbdcp.gov.in/index4.php?lang=1&level=0&linkid=431&lid=3715
[39]
Setthapramote C, Sasaki T, Kuhara M, et al. inventors; Google
Patents, assignee.. Dengue-virus serotype neutralizing antibodies.
[40]
Luke Robinson ZS. MyetteGregory, BabcockKarthik, Viswanathan.
inventor;. Google Patent, assignee Antibody molecules to
dengue virus and uses thereof 2015.
[41]
L’Azou M, Moureau A, Sarti E, et al. Symptomatic dengue in children in 10 Asian and Latin American countries. N Engl J Med 2016; 374(12): 1155-66.
[http://dx.doi.org/10.1056/NEJMoa1503877] [PMID: 27007959]
[http://dx.doi.org/10.1056/NEJMoa1503877] [PMID: 27007959]
[42]
Kirkpatrick BD, Durbin AP, Pierce KK, et al. Robust and Balanced immune responses to all 4 dengue virus serotypes following administration of a single dose of a live attenuated tetravalent dengue vaccine to healthy, flavivirus-naive adults. J Infect Dis 2015; 212(5): 702-10.
[http://dx.doi.org/10.1093/infdis/jiv082] [PMID: 25801652]
[http://dx.doi.org/10.1093/infdis/jiv082] [PMID: 25801652]
[43]
Manoff SB, George SL, Bett AJ, et al. Preclinical and clinical development of a dengue recombinant subunit vaccine. Vaccine 2015; 33(50): 7126-34.
[http://dx.doi.org/10.1016/j.vaccine.2015.09.101] [PMID: 26458804]
[http://dx.doi.org/10.1016/j.vaccine.2015.09.101] [PMID: 26458804]
[44]
Beckett CG, Tjaden J, Burgess T, et al. Evaluation of a prototype dengue-1 DNA vaccine in a Phase 1 clinical trial. Vaccine 2011; 29(5): 960-8.
[http://dx.doi.org/10.1016/j.vaccine.2010.11.050] [PMID: 21111785]
[http://dx.doi.org/10.1016/j.vaccine.2010.11.050] [PMID: 21111785]
[45]
Low JG, Sung C, Wijaya L, et al. Efficacy and safety of celgosivir in patients with dengue fever (CELADEN): a phase 1b, randomised, double-blind, placebo-controlled, proof-of-concept trial. Lancet Infect Dis 2014; 14(8): 706-15.
[http://dx.doi.org/10.1016/S1473-3099(14)70730-3] [PMID: 24877997]
[http://dx.doi.org/10.1016/S1473-3099(14)70730-3] [PMID: 24877997]
[46]
Nguyen NM, Tran CNB, Phung LK, et al. A randomized, double-blind placebo controlled trial of balapiravir, a polymerase inhibitor, in adult dengue patients. J Infect Dis 2013; 207(9): 1442-50.
[http://dx.doi.org/10.1093/infdis/jis470] [PMID: 22807519]
[http://dx.doi.org/10.1093/infdis/jis470] [PMID: 22807519]
[47]
Scott MSI, Joshua C, Vaikuntanath S. Ekachai Jenwitheesuk inventor;
Google Patent, assignee.. Optimized dengue virus entry inhibitory
peptide (10AN) 2011.
[48]
Setthapramote C, Sasaki T, Kuhara M, et al. Dengue-virus serotype
neutralizing antibodies. In: Google Patents. 2013.
[50]
Gracia Fe B, Yu Evb, Milagros BL, Salvador C Caoili. JB NEVADO inventor; Google Patent, assignee. Diagnosis and detection
of dengue virus infection using chicken egg antibodies 2014.
[51]
Catherine HAY SS. Bi XU inventor; Google Patent. assignee Formulation
of antibody molecules to dengue virus 2017.
[52]
JR John J. vicalvi EGH, Joseph Makowiecki inventor;. Google Patent, assignee Virus purification and formulation process 2014.
[54]
Dennis R, Burton P. vicalvi EGH, Joseph Makowiecki inventor;
Google Patent. assignee Dengue serotype 2 attenuated strain 2014.
[55]
Lai CJ, Purcell RH. Monoclonal antibodies that bind or neutralize
dengue virus. In: Google Patents. 2005.
[56]
Bosch I, SchifferlI-Hamad K, Marquez-Gomezosch J, et al. Antidengue
virus ns1 protein monoclonal antibodies. In: Google Patents. 2017.
[58]
Tan YH, Fu J, Tan BH, et al. Cdna sequence of dengue virus serotype
1 (singapore strain). In: Google Patents. 1993.
[59]
Claire YH, Kinney ETB, Richard M. Kinney inventor; Google
Patent, assignee. Chimeric west nile/dengue viruses..
[60]
Stephen S, Whitehead BRM, Kathryn A Hanley, Joseph E Blaney. Ching-Juh Lai inventor; Google Patent, assignee. Attenuated dengue
virus comprising mutations in the NS3 gene.
[61]
Stephen S, Whitehead BRM, Kathryn A Hanley, Joseph E Blaney. inventor; Google Patent. assignee Attenuated dengue virus comprising
mutations in the NS3 gene 2009.
[62]
Jill A, Livengood CYHDP, Dan T. Stinchcomb, Jorge Osorio inventor;
Google Patent, assignee. Compositions, methods and uses
for dengue virus serotype-4 constructs 2016.
[63]
Farmer L, Pitlik J, Perni R, et al. Bridged bicyclic serine protease inhibitors In: Google Patents. 2003.
[64]
Neuza Maria. Inventor. Process for preparing an attenuated tetravalent
dengue vaccine. Google patent 2003.
[65]
Chelsea MByrd. Thienopyridine derivatives for the treatment and
prevention of dengue virus infections Google patent 2012.
[66]
Spencer J. Inventor. Combinations of berberine, artemisinin,
loperamide and their derivatives to treat malaria, diarrhea, travelers'
diarrhea, dysentery, dengue fever, parasites, cholera and viruses. Google patent 2013.
[67]
Abd Kadir SL, Yaakob H, Mohamed Zulkifli R. Potential anti-dengue medicinal plants: a review. J Nat Med 2013; 67(4): 677-89.
[http://dx.doi.org/10.1007/s11418-013-0767-y] [PMID: 23591999]
[http://dx.doi.org/10.1007/s11418-013-0767-y] [PMID: 23591999]
[68]
Laille M, Gerald F, Debitus C. In vitro antiviral activity on dengue virus of marine natural products. Cell Mol Life Sci 1998; 54(2): 167-70.
[http://dx.doi.org/10.1007/s000180050138] [PMID: 9539959]
[http://dx.doi.org/10.1007/s000180050138] [PMID: 9539959]
[69]
Zhou G-C, Weng Z, Shao X, et al. Discovery and SAR studies of methionine-proline anilides as dengue virus NS2B-NS3 protease inhibitors. Bioorg Med Chem Lett 2013; 23(24): 6549-54.
[http://dx.doi.org/10.1016/j.bmcl.2013.10.071] [PMID: 24268549]
[http://dx.doi.org/10.1016/j.bmcl.2013.10.071] [PMID: 24268549]
[70]
Yin Z, Patel SJ, Wang WL, et al. Peptide inhibitors of dengue virus NS3 protease. Part 2: SAR study of tetrapeptide aldehyde inhibitors. Bioorg Med Chem Lett 2006; 16(1): 40-3.
[http://dx.doi.org/10.1016/j.bmcl.2005.09.049] [PMID: 16246563]
[http://dx.doi.org/10.1016/j.bmcl.2005.09.049] [PMID: 16246563]
[71]
Kampmann T, Yennamalli R, Campbell P, et al. In silico screening of small molecule libraries using the dengue virus envelope E protein has identified compounds with antiviral activity against multiple flaviviruses. Antiviral Res 2009; 84(3): 234-41.
[http://dx.doi.org/10.1016/j.antiviral.2009.09.007] [PMID: 19781577]
[http://dx.doi.org/10.1016/j.antiviral.2009.09.007] [PMID: 19781577]
[72]
Qaddir I, Rasool N, Hussain W, Mahmood S. Computer-aided analysis of phytochemicals as potential dengue virus inhibitors based on molecular docking, ADMET and DFT studies. J Vector Borne Dis 2017; 54(3): 255-62.
[http://dx.doi.org/10.4103/0972-9062.217617] [PMID: 29097641]
[http://dx.doi.org/10.4103/0972-9062.217617] [PMID: 29097641]
[73]
Sajin A, Rathnan R, Mechoor A. Molecular docking studies on phytocompounds from the methanol leaf extract of Carica papaya against envelope protein of dengue virus (type-2). J Comput Meth Mol Des 2015; 5(2): 1-7.
[74]
Qamar MT, Ashfaq UA, Tusleem K, et al. In-silico identification and evaluation of plant flavonoids as dengue NS2B/NS3 protease inhibitors using molecular docking and simulation approach. Pak J Pharm Sci 2017; 30(6): 2119-37.
[PMID: 29175781]
[PMID: 29175781]
[75]
Raikar S, Patil N, Kulkarni M, et al. In-silico identification and evaluation of plant flavonoids as dengue NS2B/NS3 protease inhibitors using molecular docking and simulation approach. Pak J Pharm Sci 2018; 30(6)
[76]
Anusuya S, Gromiha MM. Structural basis of flavonoids as dengue polymerase inhibitors: insights from QSAR and docking studies. J Biomol Struct Dyn 2017; 1-12.
[PMID: 29254451]
[PMID: 29254451]
[77]
Godói IP, Lima WG, Comar M Junior, et al. Docking and QM/MM studies of NS2B-NS3pro inhibitors: a molecular target against the dengue virus. . J Braz Chem Soc 2017; 28(5): 895-906.
[78]
Halim SA, Khan S, Khan A, et al. Targeting dengue virus ns-3 helicase by ligand based pharmacophore modeling and structure based virtual screening. Front Chem 2017; 5: 88.
[http://dx.doi.org/10.3389/fchem.2017.00088] [PMID: 29164104]
[http://dx.doi.org/10.3389/fchem.2017.00088] [PMID: 29164104]
[79]
Toepak E, Tambunan U, Eds. In silico design of fragment-based drug targeting host processing α-glucosidase i for dengue fever. IOP Conference Series: Materials Science and Engineering. IOP Publishing. 2017.
[80]
Powers CN, Setzer WN. An in-silico investigation of phytochemicals as antiviral agents against dengue fever. Comb Chem High Throughput Screen 2016; 19(7): 516-36.
[http://dx.doi.org/10.2174/1386207319666160506123715] [PMID: 27151482]
[http://dx.doi.org/10.2174/1386207319666160506123715] [PMID: 27151482]
[81]
Rawlinson SM, Pryor MJ, Wright PJ, Jans DA. Dengue virus RNA polymerase NS5: a potential therapeutic target? Curr Drug Targets 2006; 7(12): 1623-38.
[http://dx.doi.org/10.2174/138945006779025383] [PMID: 17168837]
[http://dx.doi.org/10.2174/138945006779025383] [PMID: 17168837]
[82]
Gallichotte EN, Baric TJ, Yount BL Jr, et al. Human dengue virus serotype 2 neutralizing antibodies target two distinct quaternary epitopes. PLoS Pathog 2018; 14(2)e1006934
[http://dx.doi.org/10.1371/journal.ppat.1006934] [PMID: 29481552]
[http://dx.doi.org/10.1371/journal.ppat.1006934] [PMID: 29481552]
[83]
Botta L, Rivara M, Zuliani V, Radi M. Drug repurposing approaches to fight Dengue virus infection and related diseases. Front Biosci 2018; 23: 997-1019.
[http://dx.doi.org/10.2741/4630] [PMID: 28930586]
[http://dx.doi.org/10.2741/4630] [PMID: 28930586]
Article Metrics
32
3
1
1