Structure-based drug design of non-nucleoside inhibitors for wild-type and drug-resistant HIV reverse transcriptase

Biochemical Pharmacology

Volumn 60, Issue 9, 2000, Pages 1251-1265

  Mao, Chen ^a   Sudbeck, Elise A ^a   Venkatachalam, T K ^a   Uckun, Fatih M ^a  

^a PARKER HUGHES INSTITUTE   (United States)

Author keywords

Drug design; Drug resistance; HIV; Molecular modeling; Non nucleoside inhibitor; Reverse transcriptase

Indexed keywords

ANTI HUMAN IMMUNODEFICIENCY VIRUS AGENT; DELAVIRDINE; EFAVIRENZ; N [2 (1 CYCLOHEXENYL)ETHYL N' [2 (5 CHLOROPYRIDYL)] THIOUREA; N [2 (2 CHLOROPHENETHYL)] N' [2 (5 BROMOPYRIDYL)] THIOUREA; N [2 (2 FLUOROPHENETHYL)] N' [2 (5 BROMOPYRIDYL)] THIOUREA; N [2 (2 THIOPHENYL)ETHYL] N' [2 (5 BROMOPYRIDYL)] THIOUREA; N [2 (2,5 DIMETHOXYPHENYLETHYL)] N' [2 (5 BROMOPYRIDYL)] THIOUREA; N [2 (4 METHYLPHENETHYL)] N' [2 (5 BROMOPYRIDYL)] THIOUREA; NEVIRAPINE; RNA DIRECTED DNA POLYMERASE INHIBITOR; UNCLASSIFIED DRUG;

ANTIVIRAL ACTIVITY; ARTICLE; DRUG DESIGN; DRUG POTENCY; DRUG STRUCTURE; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; PRIORITY JOURNAL;

AMINO ACID SUBSTITUTION; DRUG DESIGN; DRUG RESISTANCE, MICROBIAL; HIV; HIV-1 REVERSE TRANSCRIPTASE; HUMAN; MODELS, MOLECULAR; MUTATION; REVERSE TRANSCRIPTASE INHIBITORS; STRUCTURE-ACTIVITY RELATIONSHIP; THIAZOLES; TRIAZOLES;

EID: 0034333415     PISSN: 00062952     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0006-2952(00)00408-1     Document Type: Article

References (65)

1. Greene W.C. The molecular biology of human immunodeficiency virus type 1 infections. N Engl J Med. 324:1991;308-317.
2. De Clercq E. HIV inhibitors targeted at the reverse transcriptase. AIDS Res Hum Retroviruses. 8:1992;119-134.
3. Mitsuya H., Yarchoan R., Broder S. Molecular targets for AIDS therapy. Science. 249:1990;1533-1544.
4. Satcher D., Gayle H.D., De Cock K.M., Ward J.M., Fleming P.L., Metler P.R., Santas X.M. HIV/AIDS Surveillance Report. U.S. HIV and AIDS cases reported through June 1997. Hiv/Aids Surveill Rep. 9:1997;1-37.
5. Goldschmidt R.H., Dong B.J. Treatment of AIDS and HIV-related conditions - 1997. J Am Board Fam Pract. 10:1997;144-167.
6. Deeks SG and Volberding PA, HIV-1 protease inhibitors. AIDS Clin Rev 145-185, 1997-98.
7. Miles S.A. HIV infection and AIDS New biology, therapeutic advances, and clinical implications. Introduction . J Acquir Immune Defic Syndr. 16:(Suppl 1):1997;S1-S2.
8. Havlir D.V., Richman D.D. Viral dynamics of HIV Implications for drug development and therapeutic strategies . Ann Intern Med. 124:1996;984-994.
9. Grob P.M., Wu J.C., Cohen K.A., Ingraham R.H., Shih C.K., Hargrave K.D., McTague T.L., Merluzzi V.J. Nonnucleoside inhibitors of HIV-1 reverse transcriptase Nevirapine as a prototype drug . AIDS Res Hum Retroviruses. 8:1992;145-152.
10. Romero D.L., Morge R.A., Genin M.J., Biles C., Busso M., Resnick L., Althaus I.W., Reusser F., Thomas R.C., Tarpley W.G. Bis(heteroaryl)piperazine (BHAP) reverse transcriptase inhibitors Structure-activity relationships of novel substituted indole analogues and the identification of 1-[(5-methanesulfonamido-1H-indol-2-yl)-carbonyl]-4-[3- [(1-methylethyl) amino]-pyridinyl]piperazine monomethanesulfonate (U-90152S), a second-generation clinical candidate . J Med Chem. 36:1993;1505-1508.
11. Romero D.L., Olmsted R.A., Poel T.J., Morge R.A., Biles C., Keiser B.J., Kopta L.A., Friis J.M., Hosley J.D., Stefanski K.J., Wishka D.G., Evans D.B., Morris J., Stehle R.G., Sharma S.K., Yagi Y., Voorman R.L., Adams W.J., Tarpley W.G., Thomas R.C. Targeting delavirdine/atevirdine resistant HIV-1 Identification of (alkylamino)piperidine-containing bis(heteroaryl)piperazines as broad spectrum HIV-1 reverse transcriptase inhibitors . J Med Chem. 39:1996;3769-3789.
12. Esnouf R.M., Ren J., Hopkins A.L., Ross C.K., Jones E.Y., Stammers D.K., Stuart D.I. Unique features in the structure of the complex between HIV-1 reverse transcriptase and the bis(heteroaryl)piperazine (BHAP) U-90152 explain resistance mutations for this nonnucleoside inhibitor. Proc Natl Acad Sci USA. 94:1997;3984-3989.
13. Young S.D., Britcher S.F., Tran L.O., Payne L.S., Lumma W.C., Lyle T.A., Huff J.R., Anderson P.S., Olsen D.B., Carroll S.S., Pettibone D.J., O'Brien J.A., Ball R.G., Balani S.K., Lin J.H., Chen I.-W., Schleif W.A., Sardana V.V., Long W.J., Byrnes V.W., Emini E.A. L-743,726 (DMP-266) a novel, highly potent nonnucleoside inhibitor of the human immunodeficiency virus type 1 reverse transcriptase . Antimicrob Agents Chemother. 39:1995;2602-2605.
14. Danel K., Pedersen E.B., Nielsen C. Synthesis and anti-HIV-1 activity of novel 2,3-dihydro-7H-thiazolo[3,2-a]pyrimidin-7-ones. J Med Chem. 41:1998;191-198.
15. Danel K., Nielsen C., Pedersen E.B. Anti-HIV active naphthyl analogues of HEPT and DABO. Acta Chem Scand. 51:(Suppl 3):1997;426-430.
16. Danel K., Larsen E., Pedersen E.B., Vestergaard B.F., Nielsen C. Synthesis and potent anti-HIV-1 activity of novel 6-benzyluracil analogues of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine. J Med Chem. 39:1996;2427-2431.
17. Mai A., Artico M., Sbardella G., Quartarone S., Massa S., Loi A.G., De Montis A., Scintu F., Putzolu M., La Colla P. Dihydro(alkylthio)(naphthylmethyl)oxopyrimidines Novel non-nucleoside reverse transcriptase inhibitors of the S-DABO series . J Med Chem. 40:1997;1447-1454.
18. Vig R., Mao C., Venkatachalam T.K., Tuel-Ahlgren L., Sudbeck E.A., Uckun F.M. 5-Alkyl-2-[(methylthiomethyl)thio]-6-(benzyl)-pyrimidin-4-(1H)-ones as potent non-nucleoside reverse transcriptase inhibitors of S-DABO series. Bioorg Med Chem Lett. 8:1998;1461-1466.
19. Tanaka H., Baba M., Hayakawa H., Sakamaki T., Miyasaka T., Ubasawa M., Takashima H., Sekiya K., Nitta I., Shigeta S., Walker R.T., Balzarini J., De Clercq E. A new class of HIV-1-specific 6-substituted acyclouridine derivatives Synthesis and anti-HIV-1 activity of 5- or 6-substituted analogues of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) . J Med Chem. 34:1991;349-357.
20. Pontikis R., Benhida R., Aubertin A.M., Grierson D.S., Monneret C. Synthesis and anti-HIV activity of novel N-1 side chain-modified analogs of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT). J Med Chem. 40:1997;1845-1854.
21. Baba M., Shigeta S., Tanaka H., Miyasaka T., Ubasawa M., Umezu K., Walker R.T., Pauwels R., De Clercq E. Highly potent and selective inhibition of HIV-1 replication by 6-phenylthiouracil derivatives. Antiviral Res. 17:1992;245-264.
22. Ding J., Das K., Moereels H., Koymans L., Andries K., Janssen P.A., Hughes S.H., Arnold E. Structure of HIV-1 RT/TIBO R 86183 complex reveals similarity in the binding of diverse nonnucleoside inhibitors. Nat Struct Biol. 2:1995;407-415.
23. Balzarini J., Pérez-Pérez M.-J., San-Félix A., Schols D., Perno C.-F., Vandamme A.-M., Camarasa M.-J., De Clercq E. 2′,5′-Bis-O-(tert-butyldimethylsilyl)-3′-spiro-5″- (4″-amino-1″,2″- oxathiole-2″,2″-dioxide)pyrimidine (TSAO) nucleoside analogues Highly selective inhibitors of human immunodeficiency virus type 1 that are targeted at the viral reverse transcriptase . Proc Natl Acad Sci USA. 89:1992;4392-4396.
24. Balzarini J. Novel concepts in the treatment of human immunodeficiency virus type 1 (HIV-1) infections by HIV-1-specific reverse transcriptase inhibitors. Verh K Acad Geneeskd Belg. 57:1995;575-600.
25. Buckheit J.R.W., Kinjerski T.L., Fliakas-Boltz V., Russell J.D., Stup T.L., Pallansch L.A., Brouwer W.G., Dao D.C., Harrison W.A., Schultz R.J., Bader J.P., Yang S.S. Structure-activity and cross-resistance evaluations of a series of human immunodeficiency virus type-1-specific compounds related to oxathiin carboxanilide. Antimicrob Agents Chemother. 39:1995;2718-2727.
26. Buckheit R.W. Jr, Snow M.J., Fliakas-Boltz V., Kinjerski T.L., Russell J.D., Pallansch L.A., Brouwer W.G., Yang S.S. Highly potent oxathiin carboxanilide derivatives with efficacy against nonnucleoside reverse transcriptase inhibitor-resistant human immunodeficiency virus isolates. Antimicrob Agents Chemother. 41:1997;831-837.
27. Buckheit R.W. Jr, Hollingshead M., Stinson S., Fliakas-Boltz V., Pallansch L.A., Roberson J., Decker W., Elder C., Borgel S., Bonomi C., Shores R., Siford T., Malspeis L., Bader J.P. Efficacy, pharmacokinetics, and in vivo antiviral activity of UC781, a highly potent, orally bioavailable nonnucleoside reverse transcriptase inhibitor of HIV type 1. AIDS Res Hum Retroviruses. 13:1997;789-796.
28. Font M., Monge A., Alvarez E., Cuartero A., Losa M.J., Fidalgo M.J., SanMartin C., Nadal E., Ruiz I., Merino I., Martinez-Irujo J.J., Alberdi E., Santiago E., Prieto I., Lasarte J.J., Sarobe P., Borras F. Synthesis and evaluation of new Reissert analogs as HIV-1 reverse transcriptase inhibitors. 1. Quinoline and quinoxaline derivatives. Drug Des Disc. 14:1997;305-332.
29. Kleim J.P., Rosner M., Winkler I., Paessens A., Kirsch R., Hsiou Y., Arnold E., Riess G. Selective pressure of a quinoxaline nonnucleoside inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) on HIV-1 replication results in the emergence of nucleoside RT-inhibitor-specific (RT Leu-74→Val or Ile and Val-75→Leu or Ile) HIV-1 mutants. Proc Natl Acad Sci USA. 93:1996;34-38.
30. Fujiwara M., Ijichi K., Hanasaki Y., Ide T., Katsuura K., Takayama H., Aimi N., Shigeta S., Konno K., Yokota T., Baba M. Thiadiazole derivatives Highly potent and selective inhibitors of human immunodeficiency virus type 1 (HIV-1) replications in vitro . Microbiol Immunol. 41:1997;301-308.
31. Bell F.W., Cantrell A.S., Hogberg M., Jaskunas S.R., Johansson N.G., Jordan C.L., Kinnick M.D., Lind P., Morin J.M. Jr, Noreen R., Oberg B., Palkowitz J.A., Parrish C.A., Pranc P., Sahlberg C., Ternansky R.T., Vasileff R.T., Vrang L., West S.J., Zhang H., Zhou X.X. Phenethylthiazolethiourea (PETT) compounds, a new class of HIV-1 reverse transcriptase inhibitors. 1. Synthesis and basic structure-activity relationship studies of PETT analogs. J Med Chem. 38:1995;4929-4936.
32. Cantrell A.S., Engelhardt P., Hogberg M., Jaskunas S.R., Johansson N.G., Jordan C.L., Kangasmetsa J., Kinnick M.D., Lind P., Morin J.M. Jr, Muesing M.A., Noreen R., Oberg B., Pranc P., Sahlberg C., Ternansky R.J., Vasileff R.T., Vrang L., West S.J., Zhang H. Phenethylthiazolylthiourea (PETT) compounds as a new class of HIV-1 reverse transcriptase inhibitors. 2. Synthesis and further structure-activity relationship studies of PETT analogs. J Med Chem. 39:1996;4261-4274.
33. Ahgren C., Backro K., Bell F.W., Cantrell A.S., Clemens M., Colacino J.M., Deeter J.B., Engelhardt J.A., Hogberg M., Jaskunas S.R., Johansson N.G., Jordan C.L., Kasher J.S., Kinnick M.D., Lind P., Lopez C., Morin J.M.J., Muesing M.A., Noreen R., Oberg B., Paget C.J., Palkowitz J.A., Parrish C.A., Pranc P., Rippy M.K., Rydergard C., Sahlberg C., Swanson S., Ternansky R.J., Unge T., Vasileff R.T., Vrang L., West S.J., Zhang H., Zhou X.X. The PETT series, a new class of potent nonnucleoside inhibitors of human immunodeficiency virus type 1 reverse transcriptase. Antimicrob Agents Chemother. 39:1995;1329-1335.
34. Heinisch G., Matuszczak B., Pachler S., Rakowitz D. The inhibitory activity of diazinyl-substituted thiourea derivatives on human immunodeficiency virus type 1 reverse transcriptase. Antiviral Chem Chemother. 8:1997;443-446.
35. Huang H., Chopra R., Verdine G.L., Harrison S.C. Structure of a covalently trapped catalytic complex of HIV-1 reverse transcriptase Implications for drug resistance . Science. 282:1998;1669-1675.
36. Joyce C.M., Steitz T.A. Function and structure relationships in DNA polymerases. Annu Rev Biochem. 63:1994;777-822.
37. Joyce C.M., Steitz T.A. Polymerase structures and function Variations on a theme? J Bacteriol. 177:1995;6321-6329.
38. Steitz T.A., Smerdon S.J., Jager J., Joyce C.M. A unified polymerase mechanism for nonhomologous DNA and RNA polymerases. Science. 266:1994;2022-2025.
39. Brautigam C.A., Steitz T.A. Structural and functional insights provided by crystal structures of DNA polymerases and their substrate complexes. Curr Opin Struct Biol. 8:1998;54-63.
40. Kohlstaedt L.A., Wang J., Friedman J.M., Rice P.A., Steitz T.A. Crystal structure at 3.5 Å resolution of HIV-1 reverse transcriptase complexed with an inhibitor. Science. 256:1992;1783-1790.
41. Smerdon S.J., Jager J., Wang J., Kohlstaedt L.A., Chirino A.J., Friedman J.M., Rice P.A., Steitz T.A. Structure of the binding site for nonnucleoside inhibitors of the reverse transcriptase of human immunodeficiency virus type 1. Proc Natl Acad Sci USA. 91:1994;3911-3915.
42. Ren J., Esnouf R., Garman E., Somers D., Ross C., Kirby I., Keeling J., Darby G., Jones Y., Stuart D., Stammers D. High resolution structures of HIV-1 RT from four RT-inhibitor complexes. Nat Struct Biol. 2:1995;293-302.
43. Ding J., Das K., Tantillo C., Zhang W., Clark A.D. Jr, Jessen S., Lu X., Hsiou Y., Jacobo-Molina A., Andries K., Pauwels R., Moereels H., Koymans L., Janssen P.A.J., Smith R.H.J., Kroeger Koepke R., Michejda C.J., Hughes S.H., Arnold E. Structure of HIV-1 reverse transcriptase in a complex with the non-nucleoside inhibitor α-APA R 95845 at 2.8 Å resolution. Structure. 3:1995;365-379.
44. Ren J., Esnouf R., Hopkins A., Ross C., Jones Y., Stammers D., Stuart D. The structure of HIV-1 reverse transcriptase complexed with 9-chloro-TIBO Lessons for inhibitor design . Structure. 3:1995;915-926.
45. Hirsch MS, Conway B, D'Aquila RT, Johnson VA, Brun-Vézinet F, Clotet B, Demeter LM, Hammer SM, Jacobsen DM, Kuritzkes DR, Loveday C, Mellors JW, Vella S and Richman DD for the International AIDS Society - USA Panel, Antiretroviral drug resistance testing in adults with HIV infection: Implications for clinical management. JAMA 279: 1984-1991, 1998.
46. Connolly M.L. Solvent-accessible surfaces of proteins and nucleic acids. Science. 221:1983;709-713.
47. InsightII, Molecular Simulations Inc., San Diego, CA, 1996.
48. De Clercq E. Toward improved anti-HIV chemotherapy Therapeutic strategies for intervention with HIV infections . J Med Chem. 38:1995;2491-2517.
49. De Clercq E. The role of non-nucleoside reverse transcriptase inhibitors (NNRTIs) in the therapy of HIV-1 infection. Antiviral Res. 38:1998;153-179.
50. De Clercq E. Perspectives of non-nucleoside reverse transcriptase inhibitors (NNRTIs) in the therapy of HIV-1 infection. Farmaco. 54:1999;26-45.
51. Hopkins A.L., Ren J., Esnouf R.M., Willcox B.E., Jones E.Y., Ross C., Miyasaka T., Walker R.T., Tanaka H., Stammers D.K., Stuart D.I. Complexes of HIV-1 reverse transcriptase with inhibitors of the HEPT series reveal conformational changes relevant to the design of potent non-nucleoside inhibitors. J Med Chem. 39:1996;1589-1600.
52. Tantillo C., Ding J., Jacobo-Molina A., Nanni R.G., Boyer P.L., Hughes S.H., Pauwels R., Andries K., Janssen P.A., Arnold E. Locations of anti-AIDS drug binding sites and resistance mutations in the three-dimensional structure of HIV-1 reverse transcriptase. Implications for mechanisms of drug inhibition and resistance. J Mol Biol. 243:1994;369-387.
53. Hsiou Y., Das K., Ding J., Clark A.D. Jr, Kleim J.-P., Rösner M., Winkler I., Riess G., Hughes S.H., Arnold E. Structures of Tyr188Leu mutant and wild-type HIV-1 reverse transcriptase complexed with the non-nucleoside inhibitor HBY 097 Inhibitor flexibility is a useful design feature for reducing drug resistance . J Mol Biol. 284:1998;313-323.
54. Mao C., Vig R., Venkatachalam T.K., Sudbeck E.A., Uckun F.M. Structure-based design of N-[2-(1-piperidinylethyl)]-N′-[2-(5-bromopyridyl)]-thiourea and N-[2-(1-piperazinylethyl)]-N′-[2-(5-bromopyridyl)]-thiourea as potent non-nucleoside inhibitors of HIV-1 reverse transcriptase. Bioorg Med Chem Lett. 8:1998;2213-2218.
55. Vig R., Mao C., Venkatachalam T.K., Tuel-Ahlgren L., Sudbeck E.A., Uckun F.M. Rational design and synthesis of phenethyl-5-bromopyridyl thiourea derivatives as potent non-nucleoside inhibitors of HIV reverse transcriptase. Bioorg Med Chem. 6:1998;1789-1797.
56. Sudbeck E.A., Mao C., Vig R., Venkatachalam T.K., Tuel-Ahlgren L., Uckun F.M. Structure-based design of novel dihydroalkoxybenzyloxopyrimidine derivatives as potent nonnucleoside inhibitors of the human immunodeficiency virus reverse transcriptase. Antimicrob Agents Chemother. 42:1998;3225-3233.
57. Mao C., Sudbeck E.A., Venkatachalam T.K., Uckun F.M. Rational design of N-[2-(2,5-dimethoxyphenylethyl)]-N′-[2-(5-bromopyridyl)]-thiourea (HI-236) as a potent non-nucleoside inhibitor of drug-resistant human immunodeficiency virus. Bioorg Med Chem Lett. 9:1999;1593-1598.
58. Uckun F.M., Chelstrom L.M., Tuel-Ahlgren L., Dibirdik I., Irvin J.D., Chandan-Langlie M., Myers D.E. TXU (anti-CD7)-pokeweed antiviral protein as a potent inhibitor of human immunodeficiency virus. Antimicrob Agents Chemother. 42:1998;383-388.
59. + cells by monoclonal antibodies. Nature. 347:1990;92-95.
60. Jain A.N. Scoring noncovalent protein-ligand interactions A continuous differentiable function tuned to compute binding affinities . J Comput Aided Mol Des. 10:1996;427-440.
61. Bohm H.J. LUDI, rule-based automatic design of new substituents for enzyme inhibitor leads. J Comput Aided Mol Des. 6:1992;593-606.
62. Bohm H.J. The development of a simple empirical scoring function to estimate the binding constant for a protein-ligand complex of known three-dimensional structure. J Comput Aided Mol Des. 8:1994;243-256.
63. Uckun F.M., Mao C., Pendergrass S., Maher D., Zhu D., Tuel-Ahlgren L., Venkatachalam T.K. N-[2-(1-cyclohexenyl)ethyl]-N′-[2-(5-bromopyridyl)]-thiourea and N′-[2-(1-cyclohexenyl)ethyl]-N′-[2-(5-chloropyridyl)]-thiourea as potent inhibitors of multidrug-resistant human immunodeficiency virus-1. Bioorg Med Chem Lett. 9:1999;2721-2726.
64. Kroeger Smith M.B., Rouzer C.A., Taneyhill L.A., Smith N.A., Hughes S.H., Boyer P.L., Janssen P.A., Moereels H., Koymans L., Arnold E., Ding J., Das K., Zhang W., Michejda C.J., Smith R.H. Molecular modeling studies of HIV-1 reverse transcriptase nonnucleoside inhibitors Total energy of complexation as a predictor of drug placement and activity . Prot Sci. 4:1995;2203-2222.
65. Uckun F.M., Pendergrass S., Maher D., Zhu D., Tuel-Ahlgren L., Mao C., Venkatachalam T.K. N-[2-(2-Thiophene) ethyl]-N′-[2-(5-bromopyridyl)] thiourea as a potent inhibitor of NNI-resistant and multidrug-resistant human immunodeficiency virus-1. Bioorg Med Chem Lett. 9:1999;3411-3416.