Drug design for flavivirus proteases: What are we missing?

Current Pharmaceutical Design

Volumn 20, Issue 21, 2014, Pages 3422-3427

  Poulsen, Anders ^a   Kang, Congbao ^a   Keller, Thomas H ^a  

^a Agency for Science   (Singapore)

Author keywords

Dengue virus; Flaviviral protease; Hepatitis C virus; NS3 protease; West nile virus

Indexed keywords

BOCEPREVIR; DENGUE VIRUS PROTEASE; HEPATITIS C VIRUS PROTEASE; NONSTRUCTURAL PROTEIN 3; PEPTIDOMIMETIC AGENT; PROTEINASE; TELAPREVIR; UNCLASSIFIED DRUG; WEST NILE FLAVIVIRUS PROTEASE; ANTIVIRUS AGENT; NS3 PROTEIN, FLAVIVIRUS; RNA HELICASE; SERINE PROTEINASE; VIRUS PROTEIN;

BINDING SITE; CONFORMATIONAL TRANSITION; DENGUE VIRUS; DRUG DESIGN; ENZYME ACTIVITY; ENZYME CONFORMATION; HEPATITIS C VIRUS; HIGH THROUGHPUT SCREENING; LIGAND BINDING; NEGLECTED DISEASE; NONHUMAN; PRIORITY JOURNAL; PROTEIN ANALYSIS; PROTEIN STRUCTURE; REVIEW; WEST NILE FLAVIVIRUS; ANTAGONISTS AND INHIBITORS; CHEMICAL STRUCTURE; DRUG EFFECTS; ENZYMOLOGY; FLAVIVIRUS; HEPACIVIRUS; HUMAN; MOLECULARLY TARGETED THERAPY; PROCEDURES;

ANTIVIRAL AGENTS; BINDING SITES; DENGUE VIRUS; DRUG DESIGN; FLAVIVIRUS; HEPACIVIRUS; HUMANS; MODELS, MOLECULAR; MOLECULAR TARGETED THERAPY; RNA HELICASES; SERINE ENDOPEPTIDASES; VIRAL NONSTRUCTURAL PROTEINS; WEST NILE VIRUS;

EID: 84903697119     PISSN: 13816128     EISSN: 18734286     Source Type: Journal    
DOI: 10.2174/13816128113199990633     Document Type: Review

References (50)

1. Lindenbach BD, Thiel HJ, Rice CM. Flaviviridae: The Viruses and Their Replication. Fields Virology, 5th Edition. Lippincott-Raven Publishers, Philadelphia 2007: 1101-52.
2. Barrett AD, Monath TP, Barban V, Niedrig M, Teuwen DE. 17D yellow fever vaccines: new insights. A report of a workshop held during the World Congress on medicine and health in the tropics, Marseille, France, Monday 12 September 2005. Vaccine 2007; 25: 2758-65.
3. Barrett AD, Teuwen DE. Yellow fever vaccine-how does it work and why do rare cases of serious adverse events take place? Curr Opin Immunol 2009; 21: 308-13.
4. Noble CG, Chen YL, Dong H, et al. Strategies for development of Dengue virus inhibitors. Antiviral Res 2010; 85: 450-62.
5. Stoermer MJ, Chappell KJ, Liebscher S, et al. Potent cationic inhibitors of West Nile Virus NS2B/NS3 protease with serum stability, cell permeability and antiviral activity. J Med Chem 2008; 51: 5714-21.
6. Leung D, Abbenante G, Fairlie DP. Protease inhibitors: current status and future prospects. J Med Chem 2000; 43: 305-41.
7. Fear G, Komarnytsky S, Raskin I. Protease inhibitors and their peptidomimetic derivatives as potential drugs. Pharmacol Ther 2007; 113: 354-68.
8. Qiu X, Liu ZP. Recent developments of peptidomimetic HIV-1 protease inhibitors. Curr Med Chem 2011; 18: 4513-37.
9. Tsantrizos YS. Peptidomimetic therapeutic agents targeting the protease enzyme of the human immunodeficiency virus and hepatitis C virus. Acc Chem Res 2008; 41: 1252-63.
10. Robin G, Chappell K, Stoermer MJ, et al. Structure of West Nile virus NS3 protease: ligand stabilization of the catalytic conformation. J Mol Biol 2009; 385: 1568-77.
11. 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: 372-3.
12. Nair LG, Sannigrahi M, Bogen S, et al. P4 capped amides and lactams as HCV NS3 protease inhibitors with improved potency and DMPK profile. Bioorg Med Chem Lett 2010; 20: 567-70.
13. Aleshin AE, Shiryaev SA, Strongin AY, Liddington RC. Structural evidence for regulation and specificity of flaviviral proteases and evolution of the Flaviviridae fold. Protein Sci 2007; 16: 795-806.
14. 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: 3059-67.
15. Noble CG, Seh CC, Chao AT, Shi PY. Ligand-bound structures of the dengue virus protease reveal the active conformation. J Virol 2012; 86: 438-46.
16. Assenberg R, Mastrangelo E, Walter TS, et al. Crystal structure of a novel conformational state of the flavivirus NS3 protein: implications for polyprotein processing and viral replication. J Virol 2009; 83: 12895-906.
17. Luo D, Xu T, Hunke C, Gruber G, Vasudevan SG, Lescar J. Crystal structure of the NS3 protease-helicase from dengue virus. J Virol 2008; 82: 173-83.
18. Luo D, Wei N, Doan DN, et al. Flexibility between the protease and helicase domains of the dengue virus NS3 protein conferred by the linker region and its functional implications. J Biol Chem 2010; 285: 18817-27.
19. Venkatraman S, Njoroge FG. Macrocyclic inhibitors of HCV NS3-4A protease: design and structure activity relationship. Curr Top Med Chem 2007; 7: 1290-301.
20. Arias CF, Preugschat F, Strauss JH. Dengue 2 virus NS2B and NS3 form a stable complex that can cleave NS3 within the helicase domain. Virology 1993; 193: 888-99.
21. Su XC, Ozawa K, Qi R, Vasudevan SG, Lim SP, Otting G. NMR analysis of the dynamic exchange of the NS2B cofactor between open and closed conformations of the West Nile virus NS2B-NS3 protease. PLoS Negl Trop Dis 2009; 3: e561.
22. de la Cruz L, Nguyen TH, Ozawa K, Shin J, Graham B, Huber T, Otting G. Binding of low molecular weight inhibitors promotes large conformational changes in the dengue virus NS2B-NS3 protease: fold analysis by pseudocontact shifts. J Am Chem Soc 2011; 133: 19205-15.
23. Gayen S, Chen AS, Huang Q, Kang C. West Nile Virus (WNV) protease and membrane interactions revealed by NMR spectroscopy. Biochem Biophys Res Commun 2012; 423: 799-804.
24. Saalau-Bethell SM, Woodhead AJ, Chessari G, et al. Discovery of an allosteric mechanism for the regulation of HCV NS3 protein function. Nat Chem Biol 2012; 8: 920-5.
25. Morikawa K, Lange CM, Gouttenoire J, et al. Nonstructural protein 3-4A: the Swiss army knife of hepatitis C virus. J Viral Hepat 2011; 18: 305-15.
26. Kim JL, Morgenstern KA, Lin C, et al. Crystal structure of the hepatitis C virus NS3 protease domain complexed with a synthetic NS4A cofactor peptide. Cell 1996; 87: 343-55.
27. Love RA, Parge HE, Wickersham JA, et al. The crystal structure of hepatitis C virus NS3 proteinase reveals a trypsin-like fold and a structural zinc binding site. Cell 1996; 87: 331-42.
28. Love RA, Parge HE, Wickersham JA, et al. The conformation of hepatitis C virus NS3 proteinase with and without NS4A: a structural basis for the activation of the enzyme by its cofactor. Clin Diagn Virol 1998; 10: 151-6.
29. Neddermann P, Tomei L, Steinkuhler C, Gallinari P, Tramontano A, De Francesco R. The nonstructural proteins of the hepatitis C virus: structure and functions. Biol Chem 1997; 378: 469-76.
30. Barbato G, Cicero DO, Nardi MC, et al. The solution structure of the N-terminal proteinase domain of the hepatitis C virus (HCV) NS3 protein provides new insights into its activation and catalytic mechanism. J Mol Biol 1999; 289: 371-84.
31. Kang C, Gayen S, Wang W, et al. Exploring the binding of peptidic West Nile virus NS2B-NS3 protease inhibitors by NMR. Antiviral Res 2013; 97: 137-44.
32. Kim YM, Gayen S, Kang C, et al. NMR Analysis of a Novel Enzymatically Active Unlinked Dengue NS2B-NS3 Protease Complex. J Biol Chem 2013; 288: 12891-900.
33. Steinkuhler C, Biasiol G, Brunetti M, et al. Product inhibition of the hepatitis C virus NS3 protease. Biochemistry 1998; 37: 8899-905.
34. Llinas-Brunet M, Bailey M, Fazal G, et al. Peptide-based inhibitors of the hepatitis C virus serine protease. Bioorg Med Chem Lett 1998; 8: 1713-8.
35. Llinas-Brunet M, Bailey M, Fazal G, et al. Highly potent and selective peptide-based inhibitors of the hepatitis C virus serine protease: towards smaller inhibitors. Bioorg Med Chem Lett 2000; 10: 2267-70.
36. Llinas-Brunet M, Bailey MD, Goudreau N, et al. Discovery of a potent and selective noncovalent linear inhibitor of the hepatitis C virus NS3 protease (BI 201335). J Med Chem 2010; 53: 6466-76.
37. Tsantrizos YS, Bolger G, Bonneau P, et al. Macrocyclic inhibitors of the NS3 protease as potential therapeutic agents of hepatitis C virus infection. Angew Chem Int Ed Engl 2003; 42: 1356-60.
38. Llinas-Brunet M, Bailey M, Deziel R, et al. Studies on the Cterminal of hexapeptide inhibitors of the hepatitis C virus serine protease. Bioorg Med Chem Lett 1998; 8: 2719-24.
39. Warheads mimic the transition state upon binding to the enzyme. This provides a lot of binding energy, allowing for an overall reducition of the molecular weight of the inhibitor. See reference 40 for a detailed scientific explanation.
40. Lienhard GE. Enzymatic catalysis and transition-state theory. Science 1973; 180: 149-54.
41. Njoroge FG, Chen KX, Shih NY, Piwinski JJ. Challenges in modern drug discovery: a case study of boceprevir, an HCV protease inhibitor for the treatment of hepatitis C virus infection. Acc Chem Res 2008; 41: 50-9.
42. Kwong AD, Kauffman RS, Hurter P, Mueller P. Discovery and development of telaprevir: an NS3-4A protease inhibitor for treating genotype 1 chronic hepatitis C virus. Nat Biotechnol 2011; 29: 993-1003.
43. Yusof R, Clum S, Wetzel M, Murthy HM, Padmanabhan R. Purified NS2B/NS3 serine protease of dengue virus type 2 exhibits cofactor NS2B dependence for cleavage of substrates with dibasic amino acids in vitro. J Biol Chem 2000; 275: 9963-9.
44. Li J, Lim SP, Beer D, et al. Functional profiling of recombinant NS3 proteases from all four serotypes of dengue virus using tetrapeptide and octapeptide substrate libraries. J Biol Chem 2005; 280: 28766-74.
45. Chappell KJ, Stoermer MJ, Fairlie DP, Young PR. Insights to substrate binding and processing by West Nile Virus NS3 protease through combined modeling, protease mutagenesis, and kinetic studies. J Biological Chem 2006; 281: 38448-58.
46. Chanprapaph S, Saparpakorn P, Sangma C, et al. Competitive inhibition of the dengue virus NS3 serine protease by synthetic peptides representing polyprotein cleavage sites. Biochem Biophys Res Commun 2005; 330: 1237-46.
47. Kang C, Gayen S, Wang W, et al. Exploring the binding of peptidic West Nile virus NS2B-NS3 protease inhibitors by NMR. Antiviral Res 2012.
48. Hammamy MZ, Haase C, Hammami M, Hilgenfeld R, Steinmetzer T. Development and characterization of new peptidomimetic inhibitors of the West Nile virus NS2B-NS3 protease. Chem Med Chem 2013; 8: 231-41.
49. Perola E, Herman L, Weiss J. Development of a Rule-Based Method for the Assessment of Protein Druggability. J Chem Inf Model 2012.
50. Halgren TA. Identifying and characterizing binding sites and assessing druggability. J Chem Inf Model 2009; 49: 377-89.