Molecular interactions of CCR5 with major classes of small-molecule anti-HIV CCR5 antagonists

Molecular Pharmacology

Volumn 73, Issue 3, 2008, Pages 789-800

  Kondru, Rama ^a   Zhang, Jun ^a   Ji, Changhua ^a   Mirzadegan, Tara ^a   Rotstein, David ^a   Sankuratri, Surya ^a   Dioszegi, Marianna ^a  

^a Roche Palo Alto ^*  (United States)

Author keywords

[No Author keywords available]

Indexed keywords

1 ACETYL N [3 [4 (4 CARBAMOYLBENZYL) 1 PIPERIDINYL]PROPYL] N (3 CHLORO 4 METHYLPHENYL) 4 PIPERIDINECARBOXAMIDE; AMINO ACID; APLAVIROC; CHEMOKINE RECEPTOR CCR5; CHEMOKINE RECEPTOR CCR5 ANTAGONIST; HUMAN IMMUNODEFICIENCY VIRUS ANTIBODY; MARAVIROC; MEMBRANE PROTEIN; N [4 [[[6,7 DIHYDRO 2 (4 METHYLPHENYL) 5H BENZOCYCLOHEPTEN 8 YL]CARBONYL]AMINO]BENZYL] N,N DIMETHYL 2H TETRAHYDROPYRAN 4 AMINIUM CHLORIDE; NITROGEN; VICRIVIROC;

ANTIVIRAL ACTIVITY; ARTICLE; DRUG DESIGN; DRUG STRUCTURE; HUMAN; MOLECULAR INTERACTION; NONHUMAN; NUCLEOTIDE SEQUENCE; PRIORITY JOURNAL; PROTEIN BINDING;

AMIDES; AMINO ACID SEQUENCE; ANIMALS; ANTI-HIV AGENTS; BENZOATES; BINDING SITES; CHO CELLS; CRICETINAE; CRICETULUS; CYCLOHEXANES; ELECTROSTATICS; HIV FUSION INHIBITORS; HIV-1; HUMANS; HYDROPHOBICITY; INHIBITORY CONCENTRATION 50; MEMBRANE FUSION; MODELS, MOLECULAR; MOLECULAR SEQUENCE DATA; MOLECULAR STRUCTURE; MUTAGENESIS, SITE-DIRECTED; PIPERAZINES; PIPERIDINES; PROTEIN STRUCTURE, SECONDARY; PROTEIN STRUCTURE, TERTIARY; PYRIMIDINES; QUATERNARY AMMONIUM COMPOUNDS; RADIOLIGAND ASSAY; RECEPTORS, CCR5; SEQUENCE HOMOLOGY, AMINO ACID; SPIRO COMPOUNDS; TRANSFECTION; TRIAZOLES;

EID: 40849098660     PISSN: 0026895X     EISSN: 15210111     Source Type: Journal    
DOI: 10.1124/mol.107.042101     Document Type: Article

References (39)

1. Baba M, Nishimura O, Kanzaki N, Okamoto M, Sawada H, Iizawa Y, Shiraishi M, Aramaki Y, Okonogi K, Ogawa Y, Meguro K, and Fujino M (1999) A small-molecule, nonpeptide CCR5 antagonist with highly potent and selective anti-HIV-1 activity. Proc Natl Acad Sci U S A 96:5698-5703.
2. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, and Bourne PE (2000) The Protein Data Bank. Nucleic Acids Res 28:235-242.
3. Blanpain C, Doranz BJ, Vakili J, Rucker J, Govaerts C, Baik SS, Lorthioir O, Migeotte I, Libert F, Baleux F, et al. (1999) Multiple charged and aromatic residues in CCR5 amino-terminal domain are involved in high affinity binding of both chemokines and HIV-1 Env protein. J Biol Chem 274:34719- 34727.
4. Bower MJ, Cohen FE, and Dunbrack RL Jr (1997) Prediction of protein side-chain rotamers from a backbone-dependent rotamer library: a new homology modeling tool. J Mol Biol 267:1268-1282.
5. Crabb C (2006) GlaxoSmithKline ends aplaviroc trials. AIDS 20:641.
6. Doranz BJ, Lu ZH, Rucker J, Zhang TY, Sharron M, Cen YH, Wang ZX, Guo HH, Du JG, Accavitti MA, et al. (1997) Two distinct CCR5 domains can mediate coreceptor usage by human immunodeficiency virus type 1. J Virol 71:6305-6314.
7. Dorr P, Westby M, Dobbs S, Griffin P, Irvine B, Macartney M, Mori J, Rickett G, Smith-Burchnell C, Napier C, et al. (2005) Maraviroc (UK-427,857), a potent, orally bioavailable, and selective small-molecule inhibitor of chemokine receptor CCR5 with broad-spectrum anti-human immunodeficiency virus type 1 activity. Antimicrob Agents Chemother 49:4721-4732.
8. Dragic T (2001) An overview of the determinants of CCR5 and CXCR4 co-receptor function. J Gen Virol 82:1807-1814.
9. Dragic T, Trkola A, Lin SW, Nagashima KA, Kajumo F, Zhao L, Olson WC, Wu L, Mackay CR, Allaway GP, et al. (1998) Amino-terminal substitutions in the CCR5 coreceptor impair gp120 binding and human immunodeficiency virus type 1 entry. J Virol 72:279-285.
10. Dragic T, Trkola A, Thompson DA, Cormier EG, Kajumo FA, Maxwell E, Lin SW, Ying W, Smith SO, Sakmar TP, et al. (2000) A binding pocket for a small molecule inhibitor of HIV-1 entry within the transmembrane helices of CCR5. Proc Natl Acad Sci U S A 97:5639-5644.
11. Farzan M, Choe H, Vaca L, Martin K, Sun Y, Desjardins E, Ruffing N, Wu L, Wyatt R, Gerard N, et al. (1998) A tyrosine-rich region in the N terminus of CCR5 is important for human immunodeficiency virus type 1 entry and mediates an association between gp120 and CCR5. J Virol 72:1160-1164.
12. Fätkenheuer G, Pozniak AL, Johnson MA, Plettenberg A, Staszewski S, Hoepelman AI, Saag MS, Goebel FD, Rockstroh JK, Dezube BJ, et al. (2005) Efficacy of short-term monotherapy with maraviroc, a new CCR5 antagonist, in patients infected with HIV-1. Nat Med 11:1170-1172.
13. Fechteler T, Dengler U, and Schomburg D (1995) Prediction of protein three-dimensional structures in insertion and deletion regions: a procedure for searching data bases of representative protein fragments using geometric scoring criteria. J Mol Biol 253:114-131.
14. Howard OM, Shirakawa AK, Turpin JA, Maynard A, Tobin GJ, Carrington M, Oppenheim JJ, and Dean M (1999) Naturally occurring CCR5 extracellular and transmembrane domain variants affect HIV-1 Co-receptor and ligand binding function. J Biol Chem 274:16228-16234.
15. Imamura S, Ichikawa T, Nishikawa Y, Kanzaki N, Takashima K, Niwa S, Iizawa Y, Baba M, and Sugihara Y (2006) Discovery of a piperidine-4-carboxamide CCR5 antagonist (TAK-220) with highly potent Anti-HIV-1 activity. J Med Chem 49: 2784-2793.
16. Ji C, Zhang J, Cammack N, and Sankuratri S (2006) Development of a novel dual CCR5-dependent and CXCR4-dependent cell-cell fusion assay system with inducible gp160 expression. J Biomol Screen 11:65-74.
17. Jones TA and Thirup S (1986) Using known substructures in protein model building and crystallography. EMBO J 5:819-822.
18. Laskowski RA, Moss DS, and Thornton JM (1993) Main-chain bond lengths and bond angles in protein structures. J Mol Biol 231:1049-1067.
19. Levitt M (1992) Accurate modeling of protein conformation by automatic segment matching. J Mol Biol 226:507-533.
20. Maeda K, Das D, Ogata-Aoki H, Nakata H, Miyakawa T, Tojo Y, Norman R, Takaoka Y, Ding J, Arnold GF, et al. (2006) Structural and molecular interactions of CCR5 inhibitors with CCR5. J Biol Chem 281:12688-12698.
21. Maeda K, Nakata H, Koh Y, Miyakawa T, Ogata H, Takaoka Y, Shibayama S, Sagawa K, Fukushima D, Moravek J, et al. (2004) Spirodiketopiperazine-based CCR5 inhibitor which preserves CC-chemokine/CCR5 interactions and exerts potent activity against R5 human immunodeficiency virus type 1 in vitro. J Virol 78:8654-8662.
22. Marozsan AJ, Kuhmann SE, Morgan T, Herrera C, Rivera-Troche E, Xu S, Baroudy BM, Strizki J, and Moore JP (2005) Generation and properties of a human immunodeficiency virus type 1 isolate resistant to the small molecule CCR5 inhibitor, SCH-417690 (SCH-D). Virology 338:182-199.
23. Mirzadegan T, Diehl F, Ebi B, Bhakta S, Polsky I, McCarley D, Mulkins M, Weatherhead GS, Lapierre JM, Dankwardt J, et al. (2000) Identification of the binding site for a novel class of CCR2b chemokine receptor antagonists: binding to a common chemokine receptor motif within the helical bundle. J Biol Chem 275: 25562-25571.
24. Morris AL, MacArthur MW, Hutchinson EG, and Thornton JM (1992) Stereochemical quality of protein structure coordinates. Proteins 12:345-364.
25. Nakata H, Maeda K, Miyakawa T, Shibayama S, Matsuo M, Takaoka Y, Ito M, Koyanagi Y, and Mitsuya H (2005) Potent anti-R5 human immunodeficiency virus type 1 effects of a CCR5 antagonist, AK602/ONO4128/GW873140, in a novel human peripheral blood mononuclear cell nonobese diabetic-SCID, interleukin-2 receptor gamma-chain-knocked-out AIDS mouse model. J Virol 79:2087-2096.
26. Nishikawa M, Takashima K, Nishi T, Furuta RA, Kanzaki N, Yamamoto Y, and Fujisawa J (2005) Analysis of binding sites for the new small-molecule CCR5 antagonist TAK-220 on human CCR5. Antimicrob Agents Chemother 49:4708-4715.
27. Palani A, Shapiro S, Josien H, Bara T, Clader JW, Greenlee WJ, Cox K, Strizki JM, and Baroudy BM (2002) Synthesis, SAR, and biological evaluation of oximinopiperidino-piperidine amides. 1. Orally bioavailable CCR5 receptor antagonists with potent anti-HIV activity. J Med Chem 45:3143-3160.
28. Rabut GE, Konner JA, Kajumo F, Moore JP, and Dragic T (1998) Alanine substitutions of polar and nonpolar residues in the amino-terminal domain of CCR5 differently impair entry of macrophage- and dualtropic isolates of human immunodeficiency virus type 1. J Virol 72:3464-3468.
29. Ross TM, Bieniasz PD, and Cullen BR (1998) Multiple residues contribute to the inability of murine CCR-5 to function as a coreceptor for macrophage-tropic human immunodeficiency virus type 1 isolates. J Virol 72:1918-1924.
30. Rucker J, Samson M, Doranz BJ, Libert F, Berson JF, Yi Y, Smyth RJ, Collman RG, Broder CC, Vassart G, et al. (1996) Regions in beta-chemokine receptors CCR5 and CCR2b that determine HIV-1 cofactor specificity. Cell 87:437-446.
31. Seibert C, Ying W, Gavrilov S, Tsamis F, Kuhmann SE, Palani A, Tagat JR, Clader JW, McCombie SW, Baroudy BM, et al. (2006) Interaction of small molecule inhibitors of HIV-1 entry with CCR5. Virology 349:41-54.
32. Seto M, Aikawa K, Miyamoto N, Aramaki Y, Kanzaki N, Takashima K, Kuze Y, Iizawa Y, Baba M, and Shiraishi M (2006) Highly potent and orally active CCR5 antagonists as anti-HIV-1 agents: synthesis and biological activities of 1-benzazocine derivatives containing a sulfoxide moiety. J Med Chem 49:2037-2048.
33. Strizki JM, Tremblay C, Xu S, Wojcik L, Wagner N, Gonsiorek W, Hipkin RW, Chou CC, Pugliese-Sivo C, Xiao Y, et al. (2005) Discovery and characterization of vicriviroc (SCH 417690), a CCR5 antagonist with potent activity against human immunodeficiency virus type 1. Antimicrob Agents Chemother 49:4911-4919.
34. Tagat JR, McCombie SW, Nazareno D, Labroli MA, Xiao Y, Steensma RW, Strizki JM, Baroudy BM, Cox K, Lachowicz J, et al. (2004) Piperazine-based CCR5 antagonists as HIV-1 inhibitors. IV. Discovery of 1-[(4,6-dimethyl-5- pyrimidinyl-)carbonyl]-4-[4-[2-methoxy-1(R)-4-(trifluoromethyl)phenyl] ethyl-3(S)-methyl-1-piperaz inyl]-4-methylpiperidine (Sch-417690/Sch-D), a potent, highly selective, and orally bioavailable CCR5 antagonist. J Med Chem 47:2405-2408.
35. Thompson JD, Higgins DG, and Gibson TJ (1994) CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res 22:4673-4680.
36. Tsamis F, Gavrilov S, Kajumo F, Seibert C, Kuhmann S, Ketas T, Trkola A, Palani A, Clader JW, Tagat JR, et al. (2003) Analysis of the mechanism by which the small-molecule CCR5 antagonists SCH-351125 and SCH-350581 inhibit human immunodeficiency virus type 1 entry. J Virol 77:5201-5208.
37. Watson C, Jenkinson S, Kazmierski W, and Kenakin T (2005) The CCR5 receptorbased mechanism of action of 873140, a potent allosteric noncompetitive HIV entry inhibitor. Mol Pharmacol 67:1268-1282.
38. Westby M, Smith-Burchnell C, Mori J, Lewis M, Mosley M, Stockdale M, Dorr P, Ciaramella G, and Perros M (2007) Reduced maximal inhibition in phenotypic susceptibility assays indicates that viral strains resistant to the CCR5 antagonist maraviroc utilize inhibitor-bound receptor for entry. J Virol 81:2359-2371.
39. Wood A and Armour D (2005) The discovery of the CCR5 receptor antagonist, UK-427,857, a new agent for the treatment of HIV infection and AIDS. Prog Med Chem 43:239-271.