New approaches to HIV protease inhibitor drug design II: Testing the substrate envelope hypothesis to avoid drug resistance and discover robust inhibitors

Current Opinion in HIV and AIDS

Volumn 3, Issue 6, 2008, Pages 642-646

  Nalam, Madhavi N L ^a   Schiffer, Celia A ^a  

^a UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL   (United States)

Author keywords

Drug resistance; HIV 1 protease; Structure based drug design; Substrate envelope

Indexed keywords

AMPRENAVIR; ATAZANAVIR; DARUNAVIR; INDINAVIR; LOPINAVIR; NELFINAVIR; PROTEINASE; PROTEINASE INHIBITOR; RITONAVIR; SAQUINAVIR; SULFONAMIDE; TIPRANAVIR;

ANTIVIRAL RESISTANCE; BINDING AFFINITY; CHEMICAL MODIFICATION; COMPETITIVE INHIBITION; CRYSTAL STRUCTURE; DRUG CONJUGATION; DRUG DESIGN; DRUG PROTEIN BINDING; DRUG SYNTHESIS; ENZYME ACTIVE SITE; ENZYME SUBSTRATE; ENZYME SUBSTRATE COMPLEX; MOLECULAR DOCKING; MOLECULAR INTERACTION; MOLECULAR MECHANICS; MOLECULAR RECOGNITION; NONHUMAN; PRIORITY JOURNAL; PROTEIN TARGETING; REVIEW; STRUCTURE ACTIVITY RELATION; VIRUS MUTATION;

EID: 67649628164     PISSN: 1746630X     EISSN: 17466318     Source Type: Journal    
DOI: 10.1097/COH.0b013e3283136cee     Document Type: Review

References (59)

1. Piot P, Feachem RG, Lee JW, Wolfensohn JD. Public health. A global response to AIDS: lessons learned, next steps. Science 2004; 304: 1909-1910.
2. Hoggs RS, O'Slaughnessy MV, Gataric N, et al. Decline in deaths from AIDS due to new antiretrovirals. Lancet 1997; 349:1294.
3. Hoggs RS, Heath KV, Yip B. Improved survival among HIV-infected individuals following initiation of antiretroviral therapy. JAMA 1998; 279:450-454.
4. Palmer S, Shafer RW, Merigan TC. Highly drug-resistant HIV-1 clinical isolates are cross-resistant to many antiretroviral compounds in current clinical development. AIDS 1999; 13:661-667.
5. Schouten JT. HIV drug resistance and the other causes of treatment failure. STEP Perspect 1997; 9:5-8.
6. Moyle GJ. Viral resistance patterns selected by antiretroviral drugs and their potential to guide treatment choice. Exp Opin Invest Drugs 1997; 6:943-964.
7. Larder BA. Viral resistance and the selection of antiretroviral combinations. J AIDS 1995; 10:S28-S33.
8. Richman DD, Staszewski S. A practical guide to HIV drug resistance and its implications for antiretroviral treatment strategies. London: Int Med Press; 1997.
9. Richman DD. Drug resistance and its implications in the management of HIV infection. Antivir Ther 1997; 2:41-58.
10. Schooley RT. Changing treatment strategies and goals. Antiviral Ther 1997; 2:59-70.
11. Vella S. HIV pathogenesis and treatment strategies. J AIDS 1995; 10:S20-S23.
12. McDonald CK, Kuritkzkes DR. Human immunodeficiency virus type 1 protease inhibitors. Arch Intern Med 1997; 157:951-959.
13. Flexner C. HIV-protease inhibitors. New Engl J Med 1998; 338:1281-1292.
14. Ji JP, Loeb LA. Fidelity of HIV-1 reverse transcriptase copying RNA in vitro. Biochemistry 1992; 31:954-958.
15. Roberts JD, Bebenek K, Kunkel TA. The accuracy of reverse transcriptase from HIV-1. Science 1988; 242:1171-1173.
16. Roberts JD, Preston BD, Johnston LA, et al. Fidelity of two retroviral reverse transcriptases during DNA-dependent DNA synthesis in vitro. Mol Cell Biol 1989; 9:469-476.
17. Wlodawer A, Erickson JW. Structure-based inhibitors of HIV-1 protease. Annu Rev Biochem 1993; 62:543-585.
18. Kim EE, Baker CT, Dwyer MD, et al. 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; 117:1181-1182.
19. Chen Z, Li Y, Chen E, et al. Crystal structure at 1.9 Angstrom resolution of human immunodeficiency virus (HIV) II protease complexed with L-735,524, and orally bioavailable inhibitor of the HIV proteases. J Biol Chem 1994; 269:26344-26348.
20. Krohn A, Redshaw S, Ritchie JC, et al. Novel binding mode of highly potent HIV-proteinase inhibitors incorporating the (R)-hydroxyethylamine isostere. J Med Chem 1991; 34:3340-3342.
21. Kaldor S, Kalish V, Davies JN, et al. Viracept (nelfinavir mesylate, AG1343): a potent, orally bioavailable inhibitor of HIV-1 protease. J Med Chem 1997; 40:3979-3985.
22. Stoll V, Qin W, Stewart KD, et al. X-ray crystallographic structure of ABT-378 (lopinavir) bound to HIV-1 protease. Bioorg Med Chem 2002; 10:2803-2806.
23. Thaisrivongs S, Strohbach JW. Structure-based discovery of tipranavir disodium (PNU-140690E): a potent, orally bioavailable, nonpeptidic HIV protease inhibitor. Biopolymers 1999; 51:51-58.
24. Kempf DJ, Marsh KC, Denissen JF, et al. ABT-538 is a potent inhibitor of human immunodeficiency virus protease and has high oral bioavailability in humans. Proc Natl Acad Sci U S A 1995; 92:2484-2488.
25. Forstenlehner M. AIDS: new FDA-approved agents. Pharm Unserer Zeit 2000; 29:58.
26. Temesgen Z. Current status of antiretroviral therapies. Expert Opin Pharmacother 2001; 2:1239-1246.
27. Shafer RW, Stevenson D, Chan B. Human immunodeficiency virus reverse transcriptase and protease sequence database. Nucleic Acids Res 1999; 27:348-352.
28. Shafer RW, Hsu P, Patick AK, et al. Identification of biased amino acid substitution patterns in human immunodeficiency virus type 1 isolates from patients treated with protease inhibitors. J Virol 1999; 73:6197-6202.
29. Wu TD, Schiffer CA, Gonzales MJ, et al. Mutation patterns and structural correlates in human immunodeficiency virus type 1 protease following different protease inhibitor treatments. J Virol 2003; 77:4836-4847.
30. Shafer RW, Schapiro JM. HIV-1 drug resistance mutations: an updated framework for the second decade of HAART. AIDS Rev 2008; 10:67-84.
31. Wang C, Mitsuya Y, Gharizadeh B, et al. Characterization of mutation spectra with ultra-deep pyrosequencing: application to HIV-1 drug resistance. Genome Res 2007; 17:1195-1201.
32. Rhee SY, Liu TF, Holmes SP, Shafer RW. HIV-1 subtype B protease and reverse transcriptase amino acid covariation. PLoS Comput Biol 2007; 3:e87.
33. Rhee SY, Fessel WJ, Zolopa AR, et al. HIV-1 protease and reverse-transcriptase mutations: correlations with antiretroviral therapy in subtype B isolates and implications for drug-resistance surveillance. J Infect Dis 2005; 192:456-465.
34. Johnston E, Winters MA, Rhee SY, et al. Association of a novel human immunodeficiency virus type 1 protease substrate cleft mutation, L23I, with protease inhibitor therapy and in vitro drug resistance. Antimicrob Agents Chemother 2004; 48:4864-4868.
35. Hoffman NG, Schiffer CA, Swanstrom R. Covariation of amino acid positions in HIV-1 protease. Virology 2003; 314:536-548.
36. Watkins T, Resch W, Irlbeck D, Swanstrom R. Selection of high-level resistance to human immunodeficiency virus type 1 protease inhibitors. Antimicrob Agents Chemother 2003; 47:759-769.
37. King NM, Prabu-Jeyabalan M, Nalivaika EA, Schiffer CA. Combating susceptibility to drug resistance: lessons from HIV-1 protease. Chem Biol 2004; 11:1333-1338.
38. Prabu-Jeyabalan M, Nalivaika EA, King NM, Schiffer CA. Viability of a drugresistant human immunodeficiency virus type 1 protease variant: structural insights for better antiviral therapy. J Virol 2003; 77:1306-1315.
39. Prabu-Jeyabalan M, Nalivaika E, Schiffer CA. Substrate shape determines specificity of recognition for HIV-1 protease: analysis of crystal structures of six substrate complexes. Structure 2002; 10:369-381.
40. Prabu-Jeyabalan M, King NM, Nalivaika EA, et al. Substrate envelope and drug resistance: crystal structure of RO1 in complex with wild-type human immunodeficiency virus type 1 protease. Antimicrob Agents Chemother 2006; 50:1518-1521.
41. Chellappan S, Kairys V, Fernandes MX, et al. Evaluation of the substrate envelope hypothesis for inhibitors of HIV-1 protease. Proteins 2007; 68:561-567. This paper describes the validation of the substrate envelope hypothesis for resistance against current inhibitors.
42. King NM, Prabu-Jeyabalan M, Nalivaika EA, et al. Structural and thermodynamic basis for the binding of TMC114, a next-generation human immunodeficiency virus type 1 protease inhibitor. J Virol 2004; 78:12012-12021.
43. Altman MD, Ali A, Reddy GS, et al. HIV-1 protease inhibitors from inverse design in the substrate envelope exhibit subnanomolar binding to drugresistant variants. J Am Chem Soc 2008; 130:6099-6113. This study shows development of novel HIV-1 protease inhibitors using the substrate envelope as a constraint.
44. Reddy GS, Ali A, Nalam MN, et al. Design and synthesis of HIV-1 protease inhibitors incorporating oxazolidinones as P2/P2' ligands in pseudosymmetric dipeptide isosteres. J Med Chem 2007; 50:4316-4328.
45. Chellappan S, Kiran Kumar Reddy GS, Ali A, et al. Design of mutationresistant HIV protease inhibitors with the substrate envelope hypothesis. Chem Biol Drug Des 2007; 69:298-313. This study shows development of novel HIV-1 protease inhibitors using the substrate envelope as a constraint with docking.
46. Ali A, Reddy GS, Cao H, et al. Discovery of HIV-1 protease inhibitors with picomolar affinities incorporating N-aryl-oxazolidinone-5- carboxamides as novel P2 ligands. J Med Chem 2006; 49:7342-7356.
47. Bandaranayake RM, Prabu-Jeyabalan M, Kakizawa J, et al. Structural analysis of human immunodeficiency virus type 1 CRF01-AE protease in complex with the substrate p1-p6. J Virol 2008; 82:6762-6766. This study is an examination of the crystal structure of a non-B HIV-1 protease.
48. Mitsuya Y, Winters MA, Fessel WJ, et al. 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; 22:1300-1305.
49. Foulkes-Murzycki JE, Scott WR, Schiffer CA. Hydrophobic sliding: a possible mechanism for drug resistance in human immunodeficiency virus type 1 protease. Structure 2007; 15:225-233. The above is a presentation of a hypothesis that could explain the role of compensatory mutations outside the active site in HIV-1 protease.
50. Prabu-Jeyabalan M, Nalivaika EA, King NM, Schiffer CA. Structural basis for coevolution of a human immunodeficiency virus type 1 nucleocapsid-p1 cleavage site with a V82A drug-resistant mutation in viral protease. J Virol 2004; 78:12446-12454.
51. Prabu-Jeyabalan M, Nalivaika EA, Romano K, Schiffer CA. Mechanism of substrate recognition by drug-resistant human immunodeficiency virus type 1 protease variants revealed by a novel structural intermediate. J Virol 2006; 80:3607-3616.
52. Kolli M, Lastere S, Schiffer CA. Co-evolution of nelfinavir-resistant HIV-1 protease and the p1-p6 substrate. Virology 2006; 347:405-409.
53. Ghosh AK, Chapsal BD, Weber IT, Mitsuya H. Design of HIV protease inhibitors targeting protein backbone: an effective strategy for combating drug resistance. Acc Chem Res 2008; 41:78-86. This study describes an alternative theory for avoiding drug resistance.
54. Wang YF, Tie Y, Boross PI, et al. Potent new antiviral compound shows similar inhibition and structural interactions with drug resistant mutants and wild type HIV-1 protease. J Med Chem 2007; 50:4509-4515. This study describes an alternative theory for avoiding drug resistance.
55. Amano M, Koh Y, Das D, et al. A novel bis- tetrahydrofuranylurethane-containing nonpeptidic protease inhibitor (PI), GRL-98065, is potent against multiple-PI-resistant human immunodeficiency virus in vitro. Antimicrob Agents Chemother 2007; 51:2143-2155.
56. Ghosh AK, Sridhar PR, Leshchenko S, et al. Structure-based design of novel HIV-1 protease inhibitors to combat drug resistance. J Med Chem 2006; 49:5252-5261.
57. Ghosh AK, Ramu Sridhar P, Kumaragurubaran N, et al. Bis-tetrahydrofuran: a privileged ligand for darunavir and a new generation of HIV protease inhibitors that combat drug resistance. ChemMedChem 2006; 1:939-950.
58. Dandache S, Sevigny G, Yelle J, et al. In vitro antiviral activity and crossresistance profile of PL-100, a novel protease inhibitor of human immunodeficiency virus type 1. Antimicrob Agents Chemother 2007; 51:4036-4043.
59. Nalam MN, Peeters A, Jonckers TH, et al. 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; 81:9512-9518.