HIV microbicides: State-of-the-art and new perspectives on the development of entry inhibitors

Future Medicinal Chemistry

Volumn 2, Issue 7, 2010, Pages 1141-1159

  Reina, Jose J ^a   Bernardi, Anna ^a   Clerici, Mario ^a,b   Rojo, Javier ^c  

^a UNIVERSITY OF MILAN   (Italy)

^b IRCCS FONDAZIONE DON CARLO GNOCCHI   (Italy)

^c UNIVERSITY OF SEVILLE   (Spain)

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; 4 BENZOYL 1 [(4 METHOXY 1H PYRROLO[2,3 B]PYRIDIN 3 YL)OXOACETYL] 2 METHYLPIPERAZINE; 8 [4 (2 BUTOXYETHOXY)PHENYL] 1,2,3,4 TETRAHYDRO 1 ISOBUTYL N [4 (1 PROPYL 1H IMIDAZOL 5 YLMETHYLSULFINYL)PHENYL] 1 BENZAZOCINE 5 CARBOXAMIDE; ANTIVIRUS AGENT; APLAVIROC; BETULIC ACID; BEVIRIMAT; CARRAGEENAN; CELLULOSE SULFATE; CHEMOKINE RECEPTOR CCR5 ANTAGONIST; CHEMOKINE RECEPTOR CXCR4 ANTAGONIST; CYANOVIRIN N; ENFUVIRTIDE; HUMAN IMMUNODEFICIENCY VIRUS FUSION INHIBITOR; IBALIZUMAB; KRH 1636; MARAVIROC; MICROBICIDE; MONOCLONAL ANTIBODY; N [3 [4 (3 BENZYL 1 ETHYL 5 PYRAZOLYL) 1 PIPERIDINYLMETHYL] 4 (3 FLUOROPHENYL)CYCLOPENTYL] N METHYLVALINE; N [4 [[[6,7 DIHYDRO 2 (4 METHYLPHENYL) 5H BENZOCYCLOHEPTEN 8 YL]CARBONYL]AMINO]BENZYL] N,N DIMETHYL 2H TETRAHYDROPYRAN 4 AMINIUM CHLORIDE; NEUTRALIZING ANTIBODY; PLERIXAFOR; PRADIMICIN A; PRO 140; PRO 2000; RAPAMYCIN; UNCLASSIFIED DRUG; UNINDEXED DRUG; VICRIVIROC; VIVAGEL;

ANTIVIRAL ACTIVITY; ANTIVIRAL THERAPY; CLINICAL RESEARCH; CLINICAL TRIAL; DRUG BIOAVAILABILITY; DRUG POTENTIATION; DRUG SCREENING; DRUG SOLUBILITY; DRUG STRUCTURE; DRUG TARGETING; HOST CELL; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS; HUMAN IMMUNODEFICIENCY VIRUS 1 INFECTION; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; NONHUMAN; PRIORITY JOURNAL; REVIEW; SEXUAL INTERCOURSE; VAGINITIS; VIRUS ENTRY; VIRUS LOAD;

ANIMALS; ANTI-INFECTIVE AGENTS; HIV FUSION INHIBITORS; HIV INFECTIONS; HIV-1; HUMANS;

EID: 77954677097     PISSN: 17568919     EISSN: None     Source Type: Journal    
DOI: 10.4155/fmc.10.203     Document Type: Review

References (142)

1. Buchbinder SP, Mehrotra DV, Duerr A et al. Efficacy assessment of a cell-mediated immunity HIV-1 vaccine (the step study): a double-blind, randomised, placebo-controlled, test-of-concept trial. Lancet 372(9653), 1881-1893 (2008).
2. Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S et al. Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand. New Engl. J. Med. 361(23), 2209-2220 (2009).
3. Balzarini J, Van Damme L. Microbicide drug candidates to prevent HIV infection. Lancet 369(9563), 787-797 (2007).
4. Cutler B, Justman J. Vaginal microbicides and the prevention of HIV transmission. Lancet Infect. Dis. 8(11), 685-697 (2008).
5. Klasse PJ, Shattock R, Moore JP. Antiretroviral drug-based microbicides to prevent HIV-1 sexual transmission. Annu. Rev. Med. 59, 455-471 (2008).
6. Grant RM, Hamer D, Hope T et al. Whither or wither microbicides? Science 321(5888), 532-534 (2008).
7. Buckeit RW Jr, Watson KM, Morrow KM, Ham AS. Development of topical microbicides to prevent the sexual transmission of HIV. Antiviral Res. 85(1), 142-158 (2010).
8. Klasse PJ, Shattock RJ, Moore JP. Which topical microbicides for blocking HIV-1 transmission will work in the real world? PLoS Med. 3(9), e351 (2006).
9. van de Wijgert JH, Shattock RJ. Vaginal microbicides: moving ahead after an unexpected setback. AIDS 21(18), 2369-2376 (2007).
10. McGowan I. Microbicides for HIV prevention: reality or hope? Curr. Opin. Infect. Dis. 23(1), 26-31 (2010).
11. Geijtenbeek TBH, Kwon DS, Torensma R et al. DC-SIGN, a dendritic cell-specific HIV-1-binding protein that enhances trans-infection of T cells. Cell 100(5), 587-597 (2000).
12. Shan M, Klasse PJ, Banerjee K et al. HIV-1 gp120 mannose induce immunosupresive responses from dendritic cells. PLoS Pathogens 3(11), e169 (2007).
13. van Kooyk Y. C-type lectins on dendritic cells: key modulators for the induction of immune responses. Biochem. Soc. Trans. 36(6), 1478-1481 (2008).
14. den Dunnen J, Gringhuis SI, Geijtenbeek T.B.H. Innate signaling by the C-type lectin DC-SIGN dictates immune responses. Cancer Immunol. Immunother. 58(7), 1149-1157 (2009).
15. Geijtenbeek TBH, den Dunnen J, Gringhuis SI. Pathogen recognition by DC-SIGN shapes adaptive immunity. Future Microbiol. 4(7), 879-890 (2009).
16. Gringhuis SI, den Dunnen J, Litjens M, van der Vlist M, Geijtenbeek TBH. Carbohydrate-specific signaling through the DC-SIGN signalosome tailors immunity to Mycobacterium tuberculosis, HIV-1 and Helicobacter pylori. Nat. Immunol. 10(10), 1081-1089 (2010).
17. den Dunnen J, Gringhuis SI, Geijtenbeek TBH. Dusting the sugar fingerprint: C-type lectin signaling in adaptive immunity. Immunol. Lett. 128(1), 12-16 (2010).
18. Ugoli S, Mondor I, Sattentau QJ. HIV-1 attachment: another look. Trends Microbiol. 7(4), 144-149 (1999).
19. Pohlmann S, Doms RW. Evaluation of current approaches to inhibit HIV entry. Curr. Drug Targ. Infect. Disor. 2(1), 9-16 (2002).
20. McKnight A, Weiss RA. Blocking the docking of HIV-1. Proc. Natl Acad. Sci. USA 100(19), 10581-10582 (2003).
21. Este JA, Telenti A. HIV entry inhibitors. Lancet 370(9581), 81-88 (2007).
22. Qian K, Morris-Natschke SL, Lee K-H. HIV entry inhibitors and their potential in HIV therapy. Med. Res. Rev. 29(2), 369-393 (2009).
23. Kuritzkes DR. HIV-1 entry inhibitors: an overview. Curr. Opin. HIV AIDS 4(2), 82-87 (2009).
24. Chisembele M, Crook A, Gafos M et al. PR02000 is ineffective in preventing HIV infection: results of the MDP301 Phase III Microbicide trial (Abstract 87LB). Presented at: CROI. San Francisco, CA, USA, 16-19 February 2010.
25. Moore JP, Sattentau QJ, Klasse PJ, Burkly LC. A monoclonal antibody to CD4 domain 2 blocks soluble CD4-induced conformational changes in the envelope glycoproteins of human immunodeficiency virus type 1 (HIV-1) and HIV-1 infection of CD4+ cells. J. Virol. 66(8), 4784-4793 (1992).
26. Kuritzkes DR, Jacobson J, Powderly WG et al. Antiretroviral activity of the anti-CD4 monoclonal antibody TNX-355 in patients infected with HIV type 1. J. Infect. Dis. 189(2), 286-291 (2004).
27. Ji C, Kopetzki E, Jekle A et al. CD4- anchoring HIV-1 fusion inhibitor with enhanced potency and in vivo stability. J. Biol. Chem. 284(8), 5175-5185 (2009).
28. Ford SL, Reddy YS, Anderson MT et al. Single-dose safety and pharmacokinetics of brecanavir, a novel human immunodeficiency virus protease inhibitor. Antimicrob. Agents Chemother. 50(6), 2201-2206 (2006).
29. Donzella GA, Schols D, Lin SW et al. AMD3100, a small molecule inhibitor of HIV-1 entry via the CXCR4 co-receptor. Nat. Med. 4(1), 72-77 (1998).
30. Ichiyama K, Yokoyama-Kumakura S, Tanaka Y et al. A duodenally absorbable CXC chemokine receptor 4 antagonist, KRH-1636, exhibits a potent and selective anti-HIV-1 activity Proc. Natl Acad. Sci. USA 100(7), 4185-4190 (2003).
31. De Clercq E. Antiviral drug discovery: ten more compounds, and ten more stories (Part B). Med. Res. Rev. 29(4), 571-610 (2009).
32. Khan A, Nicholson G, Greenman J et al. Binding optimization through coordination chemistry: CXCR4 chemokine receptor antagonists from ultrarigid metal complexes. J. Am. Chem. Soc. 131(10), 3416-3417 (2009).
33. Skerlj RT, Bridger GJ, Kaller A et al. Discovery of novel small molecule orally bioavailable C-X-C chemokine receptor 4 antagonists that are potent inhibitors of T-tropic (X4) HIV-1 replication. J. Med. Chem. 53(8), 3376-3388 (2010).
34. Gudmundsson KS, Sebahar PR, Richardson LD et al. Amine substituted N-(1H-benzimidazol-2ylmethyl)-5,6,7,8-tetrahydro-8-quinolinamines as CXCR4 antagonists with potent activity against HIV-1. Bioorg. Med. Chem. Lett. 19(17), 5048-5052 (2009).
35. Maeda K, Nakata H, Ogata H et al. The current status of, and challenges in, the development of CCR5 inhibitors as therapeutics for HIV-1 infection. Curr. Opin. Pharmacol. 4(5), 447-452 (2004).
36. Wang T, Duan Y. HIV co-receptor CCR5: structure and interactions with inhibitors. Infect. Disord. Drug Targets 9(3), 279-288 (2009).
37. Pulley SR. CCR5 antagonists: from discovery to clinical efficacy. In: Chemokine Biology -Basic Research and Clinical Application (Volume. 2). Kuldeep N, Gordon LL, Bernhard M (Eds.). Birkhauser Basel, Switzerland, 145-163 (2007).
38. Baba M, Nishimura O, Kanzaki N et al. A small-molecule, nonpeptide CCR5 antagonist with highly potent and selective anti-HIV-1 activity. Proc. Natl Acad. Sci. USA 96(10), 5698-5703 (1999).
39. Dragic T, Trkola A, Thompson DA et al. A binding pocket for a small molecule inhibitor of HIV-1 entry within the transmembrane helices of CCR5. Proc. Natl Acad. Sci. USA 97(10), 5639-5644 (2000).
40. Veazey RS, Klasse PJ, Schader SM et al. Protection of macaques from vaginal SHIV challenge by vaginally delivered inhibitors of virus-cell fusion. Nature 438(3), 99-102 (2005).
41. Schroder C, Pierson RN, Nguyen B-NH et al. CCR5 blockade modulates inflammation and alloimmunity in primates. J. Immunol. 179(4), 2289-2299 (2007).
42. Wood A, Armour D. 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 (2005).
43. Sayana S, Khanlou H. Maraviroc: a new CCR5 antagonist. Expert Rev. Anti Infect. Ther. 7(1), 9-19 (2009).
44. Taga JR, Steensma RW, McCombie SW et al. Piperazine-based CCR5 antagonists as HIV-1 inhibitors. II. Discovery of 1-[(2,4-dimethyl-3-pyridinyl) carbonyl] -4- methyl-4- [3 (S) -methyl-4- [1 (S) -[4-(trifluoro-methyl)phenyl] ethyl]-1-piperazinyl] - piperidine N1-oxide (Sch-350634), an orally bioavailable, potent CCR5 antagonist. J. Med. Chem. 44(21), 3343-3346 (2001).
45. Strizki JM. Tremblay C, Xu S et al. Discovery and characterization of vicriviroc (SCH 417690), a CCR5 antagonist with potent activity against human immunodeficiency virus type 1. Antimicrob. Agents Chemother. 49(12), 4911-4919 (2005).
46. Maeda K, Nakata H, Koh Y et al. 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(16), 8654-8662 (2004).
47. Latinovic O, Heredia A, Gallo RC, Reitz M, Le N, Redfield RR. Rapamycin enhances aplaviroc anti-HIV activity: implications for the clinical development of novel CCR5 antagonists. Antiviral Res. 83(1), 86-89 (2009).
48. Nishizawa R, Nishiyama T, Hisaichi K et al. Spirodiketopiperazine-based CCR5 antagonists: improvement of their pharmacokinetic profiles. Bioorg. Med. Chem. Lett. 20(2), 763-766 (2010).
49. Barber CG, Blakemore DC, Chiva J-Y, Eastwood RL, Middleton DS, Paradowski KA. 1-amido-1-phenyl-3-piperidinylbutanes - CCR5 antagonists for the treatment of HIV: Part 1. Bioorg. Med. Chem. Lett. 19(4), 1075-1079 (2009).
50. Barber CG, Blakemore DC, Chiva J-Y, Eastwood RL, Middleton DS, Paradowski KA. 1-amido-1-phenyl-3-piperidinylbutanes - CCR5 antagonists for the treatment of HIV: Part 2. Bioorg. Med. Chem. Lett. 19(5), 1499-1503 (2009).
51. Pryde DC, Corless M, Fenwick DR et al. The design and discovery of novel amide CCR5 antagonists. Bioorg. Med. Chem. Lett. 19(4), 1084-1088 (2009).
52. Duan M, Aquino C, Ferris R et al. [2-(4-phenyl-4-piperidinyl) ethyl] amine based CCR5 antagonists: derivatizations at the N-terminal of the piperidine ring. Bioorg. Med. Chem. Lett, 19(6), 1610-1613 (2009).
53. Duan M, Aquino C, Dorsey GF, Ferris R, Kazmierski WM. 4,4-disubstituted cyclohexylamine based CCR5 chemokine receptor antagonists as anti-HIV-1 agents. Bioorg. Med. Chem. Lett. 19(17), 4988-4992 (2009).
54. Rotstein DM, Gabriel SD, Makra F et al. Spiropiperidine CCR5 antagonists. Bioorg. Med. Chem. Lett. 19(18), 5401-5406 (2009).
55. Lemoine RC, Petersen AC, Setti L et al. Evaluation of secondary amide replacements in a series of CCR5 antagonists as a means to increase intrinsic membrane permeability. Part 1: optimization of gem-disubstituted azacycles. Bioorg. Med. Chem. Lett. 20(2), 704-708 (2010).
56. Maeda K, Das D, Ogata-Aoki H et al. Structural and molecular interactions of CCR5 inhibitors with CCR5. J. Biol. Chem. 281(18), 12688-12698 (2006).
57. Kondru R, Zhang J, Ji C et al. Molecular interactions of CCR5 with major classes of small-molecule anti-HIV CCR5 antagonists. Mol. Pharmacol. 73(3), 789-800 (2008).
58. Wang T, Duan Y. Binding modes of CCR5-targeting HIV entry inhibitors: partial and full antagonists. J. Mol. Graph. Model. 26(8), 287-295 (2008).
59. Hartley O, Gaertner H, Wilken J et al. Medicinal chemistry applied to a synthetic protein: development of highly potent HIV entry inhibitors. Proc. Natl Acad. Sci. USA 101(47), 16460-16465 (2004).
60. Trkola A, Ketas TJ, Nagashima KA et al. Potent, broad-spectrum inhibition of human immunodeficiency virus type 1 by the CCR5 monoclonal antibody PRO 140. J. Virol. 75(2), 579-588 (2001).
61. Murga JD, Franti M, Pevear DC et al. Potent antiviral synergy between monoclonal antibody and small-molecule CCR5 inhibitors of human immunodeficiency virus type 1. Antimicrob. Agents Chemother. 50(10), 3289-3296 (2006).
62. Ji C, Zhang J, Dioszegi M et al. CCR5 Small-molecule antagonists and monoclonal antibodies exert potent synergistic antiviral effects by cobinding to the receptor. Mol. Pharmacol. 72(1), 18-28 (2007).
63. Geijtenbeek TBH, Torensma R, Van Vliet SJ et al. Identification of DC-SIGN, a novel dendritic cell-specific ICAM-3 receptor that supports primary immune responses. Cell 100(5), 575-585 (2000).
64. Feinberg H, Mitchell DA, Drickamer K, Weis W. Structural basis for selective recognition of oligosaccharides by DC-SIGN and DC-SIGNR. Science 294(5549), 2163-2166 (2001).
65. Mitchell DA, Fadden AJ, Drickamer K. A novel mechanism of carbohydrate recognition by the C-type Lectins DC-SIGN and DC-SIGNR. J. Biol. Chem. 276(31), 28939-28945 (2001).
66. van Kooyk Y, Geijtenbeek TBH. DC-SIGN: escape mechanism for pathogens. Nat. Rev. Immunol. 3(9), 697-709 (2003).
67. Reina JJ, Sattin S, Invernizzi D et al. 1,2-mannobioside mimic: synthesis, DC-SIGN interaction by NMR and docking, and antiviral activity. ChemMedChem 2(7), 1030-1036 (2007).
68. Borrok MJ, Kiessling LL. Non-carbohydrate inhibitors of the lectin DC-SIGN. J. Am. Chem. Soc. 129(42), 12780-12785 (2007).
69. Mitchell DA, Jones NA, Hunter SJ et al. Synthesis of 2-C-branched derivatives of D-mannose: 2-C-aminomethyl-D-mannose binds to the human C-type lectin DC-SIGN with affinity greater than an order of magnitude compared with that of D-mannose. Tetrahedron: Asymmetry 18(12), 1502-1510 (2007).
70. Timpano G, Tabarani G, Anderluh M et al. Synthesis of novel DC-SIGN ligands with an a-fucosylamide anchor. ChemBioChem 9(12), 1921-1930 (2008).
71. Ernst B, Magnani JL. From carbohydrate leads to glycomimetic drugs. Nat. Rev. Drug Discovery 8(8), 661-677 (2009).
72. Turville SG, Santos JJ, Frank I et al. Immunodeficiency virus uptake, turnover, and 2-phase transfer in human dendritic cells. Blood 103(6), 2170-2179 (2004).
73. de Witte L, Nabatov A, Geijtenbeek TBH. Distinct roles for DC-SIGN+-dendritic cells and langerhans cells in HIV-1 transmission. Trends Mol. Med. 14(1), 12-19 (2008).
74. Kwon DS, Gregorio G, Bitton N et al. DC-SIGN-mediated internalization of HIV is required for trans-enhancement of T cell infection. Immunity 16(1), 135-144 (2002).
75. Burleigh L, Lozach P-Y, Schiffer C et al. Infection of dendritic cells (DCs), not DC-SIGN-mediated internalization of human immunodeficiency virus, is required for long-term transfer of virus to T cells. J. Virol. 80(6), 2949-2957 (2006).
76. Boggiano C, Manel N, Littman DR. Dendritic cell-mediated trans-enhancement of human immunodeficiency virus type 1 infectivity is independent of DC-SIGN. J. Virol. 81(5), 2519-2523 (2007).
77. Moris A, Nobile C, Buseyne F, Porrot F, Abastado JP, Schwartz O. DC-SIGN promotes exogenous MHC-I-restricted HIV-1 antigen presentation. Blood 103(7), 2648-2654 (2004).
78. Moris A, Pajot A, Blanchet F, Guivel-Benhassine F, Salcedo M, Schwartz O. Dendritic cells and HIV-specific CD4+ T cells: HIV antigen presentation, T-cell activation, and viral transfer. Blood 108(5), 1643-1651(2006).
79. Hodges A, Sharrocks K, Edelmann M et al. Activation of the lectin DC-SIGN induces an immature dendritic cell phenotype triggering Rho-GTPase activity required for HIV-1 replication. Nat. Immunol. 8(6), 569-577 (2007).
80. Steffen I, Tsegaye TS, Poehlmann S. Lectin-like interactions in virus-cell recognition: human immunodeficiency virus and C-type lectin interactions. In: Microbial Glycobiology, Structures, Relevance and Applications. Moran A, Holst O, Brennan P, von Itzstein M (Eds). Elsevier, NY, USA, 567-584 (2009).
81. Tabarani G, Reina JJ, Ebel C et al. Mannose hyperbranched dendritic polymers interact with clustered organization of DC-SIGN and inhibit gp120 binding. FEBSLett. 580(10), 2402-2408 (2006).
82. Rojo J, Delgado R. Glycodendritic structures: promising new antiviral drugs. J. Antimicrob. Chemother. 54(3), 579-581 (2004).
83. Lasala F, Arce E, Otero JR et al. Mannosyl glycodendritic structure inhibits DC-SIGN-mediated Ebola virus infection in cis and in trans. Antimicrob. Agents Chemother. 47(12), 3970-3972 (2003).
84. Wang S-K, Liang P-H, Astronomo RD et al. Targeting the carbohydrates on HIV-1: interaction of oligomannose dendrons with human monoclonal antibody 2G12 and DC-SIGN. Proc. Natl Acad. Sci. USA 105(10), 3690-3695 (2008).
85. Martinez-Avila O, Bedoya LM, Marradi M et al. Multivalent manno-glyconanoparticles inhibit DC-SIGN-mediated HIV-1 trans-infection of human T cells. ChemBioChem 10(11), 1806-1809 (2009).
86. Sattin S, Daghetti A, Thepaut M et al. Inhibition of DC-SIGN-mediated HIV infection by a linear trimannoside mimic in a tetravalent presentation. ACS Chem. Biol. 5(3), 301-312 (2010).
87. O'Loughlin J, Millwood IY, McDonald HM, Price CF, Kaldor JM, Paull JR. Safety, tolerability, and pharmacokinetics of SPL7013 gel (VivaGel): a dose ranging, Phase I study. Sex. Transm. Dis. 37(2),100-104 (2010).
88. Fletcher PS, Wallace GS, Mesquita PMM, Shattock RJ. Candidate polyanion microbicides inhibit HIV-1 infection and dissemination pathways in human cervical explants. Retrovirology 3, 46 (2006).
89. Van Damme L, Govinden R, Mirembe FM et al. Lack of effectiveness of cellulose 21 sulfate gel for the prevention of vaginal HIV transmission. N. Engl. J. Med. 359(5), 463-472 (2008).
90. Skoler-Karpoff S, Ramjee G, Ahmed K et al. Efficacy of Carraguard for prevention of HIV infection in women in South Africa: a randomized, double-blind, placebo-controlled trial. Lancet 372(9654), 1977-1987 (2008).
91. Sonza S, Johnson A, Tyssen D et al. Enhancement of human immunodeficiency virus type 1 replication is not intrinsic to all polyanion-based microbicides. Antimicrob. Agents Chemother. 53(8), 3565-3568 (2009).
92. Daar ES, Li XL, Moudgil T, Ho DD. High concentrations of recombinant soluble CD4 are required to neutralized primary immunodeficiency virus type 1 isolates. Proc. Natl Acad. Sci. USA 87(17), 6574-6578 (1990).
93. Haim H, Si Z, Madani N et al. Soluble CD4 and CD4-mimetic compounds inhibit HIV-1 infection by induction of a short-lived activated state. PLOS Pathogen 5(4), e1000360 (2009).
94. Fouts T, Godfrey K, Bobb K et al. Crosslinked HIV-1 envelope-CD4 receptor complexes elicit broadly cross-reactive neutralizing antibodies in rhesus macaques. Proc. Natl Acad. Sci. USA 99(18), 11842-11847 (2002).
95. Martin L, Stricher F, Misse D et al. Rational design of a CD4 mimic that inhibits HIV-1 entry and exposes cryptic neutralization epitopes. Nat. Biotech. 21(1), 71-76 (2003).
96. Baleux F, Loureiro-Morais L, Hersant Y et al. A synthetic CD4-heparan sulfate glycoconjugate inhibits CCR5 and CXCR4 HIV-1 attachment and entry. Nat. Chem. Biol. 5(10), 743-748 (2009).
97. Pantophlet R, Burton DR. Gp120: target for neutralizing HIV-1 antibodies. Annu. Rev. Immunol. 24, 739-769 (2006).
98. Phogat S, Wyatt RT, Hedestam GBK. Inhibition of HIV-1 entry by antibodies: potential viral and cellular targets. J. Intern. Med. 262(1), 26-43 (2007).
99. Buton DR, Pyati J, Koduri R et al. Efficient neutralization of primary isolates HIV-1 by a recombinant human monoclonal antibody. Science 266(5187), 1024-1027 (1994).
100. Trkola A, Purtscher M, Muster T et al. Human monoclonal antibody 2G12 defines a distinctive neutralization epitope on the gp120 glycoprotein of human immunodeficiency virus type 1. J. Virol. 70(2), 1100-1108 (1996).
101. Muster T, Steindl F, Purtscher M et al. A conserved neutralizing epitope on gp41 of human immunodeficiency virus type 1. J. Virol. 67(11), 6642-6647 (1993).
102. Kwong PD, Wilson IA. HIV-1 and influenza antibodies: seeing antigens in new ways. Nat. Immunol. 10(6), 573-578 (2009).
103. Huber M, Olson WC, Trkola A. Antibodies for HIV treatment and prevention: window of opportunity? In: Human Antibody Therapeutics for Viral Disease. Current Topics 39 in Microbiology and Immunology (volume 317). Dessain SK (Ed.) Springer-Verlag, Berlin, Heidelberg, 39-66 (2008).
104. Balzarini J. Inhibition of HIV entry by carbohydrate-binding proteins. Antiviral Res. 71(2-3), 237-247 (2006).
105. Balzarini J. Targeting the glycans of glycoproteins: a novel paradigm for antiviral therapy. Nat. Rev. Microbiol. 5(8), 583-597 (2007).
106. Boyd MR, Gustafson KR, McMahon JB et al. Discovery of cyanovirin-N, a novel human immunodeficiency virus-inactivating protein that binds viral surface envelop glycoprotein gp120: potential applications to microbicide development. Antimicrob. Agents Chemother. 41(7), 1521-1530 (1997).
107. Mori T, O'Keefe BR, Sowder II RC et al. Isolation and characterization of griffithsin, a novel HIV-inactivating protein, from the red alga Griffithsiasp. J. Biol. Chem. 280(10), 9345-9353 (2005).
108. Tsai CC, Emau P, Jiang Y et al. Cyanovirin-N inhibits AIDS virus infection in vaginal transmission models. AIDS Res. Hum. Retroviruses 20(1), 11-18 (2004).
109. Tsai CC, Emau P, Jiang Y et al. Cyanovirin-N inhibits AIDS virus infection in vaginal transmission models. AIDS Res. Hum. Retroviruses 19(7), 535-541 (2003).
110. Buffa V, Stieh D, Mamhood N, Hu Q, Fletcher P, Shattock RJ. Cyanovirin-N potently inhibits human immunodeficiency virus type 1 infection in cellular and cervical explants models. J. Gen. Virol. 90(1), 234-243 (2009).
111. Hunskens D, Vermeire K, Vandemeulebroucke E, Balzarini J, Schols D. Safety concerns for the potential use of cyanovirin-N as a microbicidal anti-HIV agent. Int. J. Biochem. Cell Biol. 40(12), 2802-2814 (2008).
112. O'Keefe BR, Vojdani F, Buffa V et al. Scaleable manufacture of HIV-1 entry inhibitor griffithsin and validation of its safety and efficacy as a topical microbicide component. Proc. Natl Acad. Sci. USA 106(15), 6099-6104 (2009).
113. Jay JI, Lai BE, Myszka DG et al. Multivalent benzoboroxole functionalized polymers as gp120 glycan targeted microbicide entry inhibitors. Mol. Pharmaceutics 7(1), 116-129 (2010).
114. Balzarini J, Van Laethem K, Daelemans D et al. Pramicidin A, a carbohydrate-binding nonpeptidic lead compound for treatment of infections with viruses with highly glycosylated envelopes, such as human immunodeficiency virus. J. Virol. 81(1), 362-373 (2007).
115. Balzarini J, Van Laethem K, Francois K et al. Pradimicin S, a highly-soluble non-peptidic small-size carbohydrate-binding antibiotic, is an anti-HIV drug lead for both microbicidal and systemic use. Antimicrob. Agents Chemother. 54(4), 1425-1435 (2010).
116. Wang T, Zhang Z, Wallace OB et al. Discovery of 4-benzoyl-1-[(4-methoxy- 1H-pyrrolo[2,3-c]-pyridin-3 -yl) oxoacetyl] -2- (R) -methylpiperazine (BMS-378806): a novel HIV-1 attachment inhibitor that interferes with CD4-gp120 interactions. J. Med. Chem. 46(20), 4236-4239 (2003).
117. Lin PF, Blair W, Wang T et al. A small molecule HIV-1 inhibitor that targets the HIV-1 envelope and inhibits CD4 receptor binding. Proc. Natl Acad. Sci. USA 100(19), 11013-11018 (2003).
118. Wang T, Yin Z, Zhang Z et al. Inhibitors of human immunodeficiency virus type 1 (HIV-1) attachment. 5. An evolution from indole to azaindoles leading to the discovery of 1-(4-benzoylpiperazin-1-yl)-2-(4,7-dimethoxy-1H-pyrrolo[2,3-c]- pyridin-3-yl)ethane-1,2-dione (BMS-488043), a drug candidate that demonstrate antiviral activity in HIV-1-infected subjects. J. Med. Chem. 52(23), 7778-7787 (2009).
119. Qadir MI, Malik SA. HIV fusion inhibitors. Rev. Med. Virol. 20(1), 23-33 (2010).
120. Moore JP, Doms RW. The entry of entry inhibitors: a fusion science and medicine. Proc. Natl Acad. Sci. USA 100(19), 10598-10602 (2003).
121. Liu S, Jing W, Cgeung B et al. HIV gp41 C-terminal heptad repeat contains multifunctional domains. J. Chem. Biol. 282(13), 9612-9620 (2007).
122. Pan C, Cai L, Lu H, Qi Z, Jiang S. Combinations of the first and next generations of human immunodeficiency virus (HIV) fusion inhibitors exhibit a highly potent synergistic effect against enfuvirtide-sensitive and-resistant HIV type 1 strains. J. Virol. 83(16), 7862-7872 (2009).
123. Ingallinella P, Bianchi E, Ladwa NA et al. Addition of a cholesterol group to an HIV-1 peptide fusion inhibitor dramatically increases its antiviral potency. Proc. Natl Acad. Sci. USA 106(14), 5801-5806 (2009).
124. Eckert DM, Malashkevich VN, Hong LH, Carr PA, Kim PS. Inhibiting HIV-1 entry: discovery of D-peptide inhibitors that target the gp41 coiled-coil pocket. Cell 99(1), 103-115 (1999).
125. Welch DB, VanDemark AP, Heroux A, Hill CP, Kay MS. Potent D-peptide inhibitors of HIV-1 entry. Proc. Natl Acad. Sci. USA 104(43), 16828-16833 (2007).
126. Mayaux JF, Bousseau A, Pauwels R et al. Triterpene derivatives that block entry of human immunodeficiency virus type 1 into cells. Proc. Natl Acad. Sci. USA 91(9), 3564-3568 (1994).
127. Lai W, Huang L, Ho P, Li Z, Montefiori D, Chen CH. Betulinic acid derivatives that target gp120 and inhibit multiple genetic subtypes of human immunodeficiency virus type 1. Antimicrob. Agents Chemother. 52(1), 128-136 (2008).
128. Baell JB, Holloway GA. New substructure filters for removal of pan assay interference compounds (PAINS) from screening libraries and for their exclusion in bioassays. J. Med. Chem. 53(7), 2719-2740 (2010).
129. Qian K, Yu D, Chen CH et al. Anti-AIDS agents. 78. Design, synthesis, metabolic stability assessment, and antiviral evaluation of novel betulinic acid derivatives as potent anti-human immunodeficiency virus (HIV) agents. J. Med. Chem. 52(10), 3248-3258 (2009).
130. Jiang S, Lu H, Liu S, Zhao Q, He Y, Debnath AK. N-substituted pyrrole derivatives as novel human immunodeficiency virus type 1 entry inhibitors that interfere with the gp41 six-helix bundle formation and block virus fusion. Antimicrob. Agents Chemother. 48(11), 4349-4359 (2004).
131. Liu K, Lu H, Hou L et al. Design, synthesis, and biological evaluation of N-carboxy-phenylpyrrole derivatives as potent HIV fusion inhibitors targeting gp41. J. Med. Chem. 51(24), 7843-7854 (2008).
132. Wang Y, Lu H, Zhu Q, Jiang S, Liao Y. Structure-based design, synthesis amd biological evaluation of new N-carboxy-phenylpyrrole derivatives as HIV fusion inhibitors targeting gp41. Bioorg. Med. Chem. Lett. 20(1), 189-192 (2010).
133. Smith PF, Ogundele A, Forrest A et al. Phase I and II study of the safety, virologic effect, and pharmacokinetics/ pharmacodynamics of single-dose 3-O-(3',3'-dimethylsuccinyl)betulinic acid (bevirimat) against human immunodeficiency virus infection. Antimicrob. Agents Chemother. 51(10), 3574-3581 (2007).
134. Stewart KD, Huth JR, Ng TI et al. Nonpeptide entry inhibitors of HIV-1 that target the gp41 coiled coil pocket. Bioorg. Med. Chem. Lett. 20(2), 612-617 (2010).
135. Ketas Thomas J, Schader SM, Zurita J et al. Entry inhibitor-based microbicides are active in vitro against HIV-1 isolates from multiple genetic subtypes. Virology 364(2), 431-440 (2007).
136. Jenabian MA, Saidi H, Charpentier C et al. In vitro synergistic activity against CCR5-tropic HIV-1 with combinations of potential candidate microbicide molecules HHA, KRV2110 and enfurvitide (T20). J. Antimicrob. Chemother. 64(6), 1192-1195 (2009).
137. Auwerx J, Francois KO, Vanstreels E et al. Capture and transmission of HIV-1 by the C-type lectin L-SIGN (DC-SIGNR) is inhibited by carbohydrate-binding agents and polyanions. Antiviral Res. 83(1), 61-70 (2009).
138. Gantlett KE, Weber JN, Sattentau QJ. Synergistic inhibition of HIV-1 infection by combinations of soluble polyanions with other potential microbicides. Antiviral Res. 75, 188-197 (2007).
139. Yeni PG, Hammer SM, Hirsch MS et al. Treatment for adult HIV infection: 2004 recommendations of the International AIDS Society-USA Panel, JAMA 292(2), 251-265 (2004).
140. Seto M, Aikawa K, Miyamoto N et al. 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(6), 2037-2048 (2006).
141. Martfnez-Avila O, Hijazi K, Marradi M et al. Gold manno- glyconanoparticles: multivalent systems to block HIV-1 gp120 binding to the lectin DC-SIGN. Chem. Eur. J. 15(38), 9874-9888 (2009).
142. AIDSMEDS www.aidsmeds.com/articles/hiv-vivrivirov-ccr5-2446-18031.html.