Volume 109, Issue 2 , Pages 94-105, February 2010
HIV-1 gp41 Fusion Intermediate: A Target for HIV Therapeutics
Article Outline
Human immunodeficiency virus (HIV)-1 infection is initiated by the binding of gp120 envelope glyco-protein to its cell receptor (CD4) and a coreceptor (CXCR4 or CCR5), followed by a series of conformational changes in the gp41 transmembrane subunit. These changes include insertion of fusion peptide into the target cell membrane and association of C-heptad repeat (CHR) peptide with the N-heptad repeat (NHR) trimer, a pre-hairpin fusion intermediate. A stable six-helix bundle core is then formed, bringing the viral envelope and target cell membrane into close proximity for fusion. Peptides derived from the CHR region, such as T20 and C34, inhibit HIV-1 fusion by interacting with the gp41 fusion intermediate. A number of anti-HIV-1 peptides and small molecule compounds targeting the gp41 NHR-trimer have been identified. By combining HIV fusion/entry inhibitors targeting different sites in the gp41 fusion intermediate, a potent synergistic effect takes place, resulting in a potential new therapeutic strategy for the HIV infection/AIDS. Here, we present an overview of the current development of anti-HIV drugs, particularly those targeting the gp41 fusion intermediate.
Key Words: fusion inhibitor , gp41 , HIV-1 , peptide , therapeutics
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References
- . HIV-1 at age 25: some thoughts for Taiwan and China . J Formos Med Assoc . 2008;107:907–908
- Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS) . Science . 1983;220:868–871
- Frequent detection and isolation of cytopathic retroviruses (HTLV-III) from patients with AIDS and at risk for AIDS . Science . 1984;224:500–503
- FDA-approved antiretrovial (ARV) drugs . Available at http://www.hivandhepatitis.com/hiv_and_aids/hiv_treat.html [Date accessed: September 14, 2009]
- . Antiviral drugs in current clinical use . J Clin Virol . 2004;30:115–133
- Drug resistance mutations in HIV-1 . Top HIV Med . 2003;11:215–221
- The prevalence of antiretroviral drug resistance in the United States . AIDS . 2004;18:1393–1401
- . Adverse effects of antiretroviral therapy . Lancet . 2000;356:1423–1430
- . Evidence that a prominent cavity in the coiled coil of HIV type 1 gp41 is an attractive drug target . Proc Natl Acad Sci USA . 1998;95:15613–15617
- . Peptide and non-peptide HIV fusion inhibitors . Curr Pharm Des . 2002;8:563–580
- Different from the HIV fusion inhibitor C34, the anti-HIV drug Fuzeon (T-20) inhibits HIV-1 entry by targeting multiple sites in gp41 and gp120 . J Biol Chem . 2005;280:11259–11273
- HIV gp41 C-terminal hep-tad repeat contains multifunctional domains: relation to mechanisms of action of anti-HIV peptides . J Biol Chem . 2007;282:9612–9620
- Rationally designed anti-HIV peptides containing multifunctional domains as molecule probes for studying the mechanisms of action of the first and second generation HIV fusion inhibitors . J Biol Chem . 2008;283:30376–30384
- . A trimeric structural domain of the HIV-1 transmembrane glycoprotein . Nat Struct Biol . 1995;2:1075–1082
- Inhibition of HIV-1 infectivity by the gp41 core: role of a conserved hydrophobic cavity in membrane fusion . J Virol . 1999;73:8578–8586
- The hydrophobic pocket contributes to the structural stability of the N-terminal coiled coil of HIV gp41 but is not required for six-helix bundle formation . Biochemistry . 2003;42:4945–4953
- Core structure of gp41 from the HIV envelope glycoprotein . Cell . 1997;89:263–273
- Atomic Structure of the Ectodomain from HIV-1 gp41 . Nature . 1997;387:426–428
- . HIV entry and its inhibition . Cell . 1998;93:681–684
- . Blocking viral entry: a complementary strategy for HIV therapy . Drug Discovery Today: Therapeutic Strategies . 2004;1:497–503
- . HIV entry inhibitors targeting gp41: from polypeptides to small-molecule compounds . Curr Pharm Design . 2007;13:143–162
- HIV-1 inhibition by a peptide . Nature . 1993;365:113
- Inhibition of HIV-1 infection by a fusion domain binding peptide from HIV-1 envelope glycoprotein gp41 . Biochem Biophys Res Commun . 1993;195:533–538
- Peptides corresponding to a predictive alpha-helical domain of human immunodeficiency virus type 1 gp41 are potent inhibitors of virus infection . Proc Natl Acad Sci USA . 1994;91:9770–9774
- . A trimeric structural subdomain of the HIV-1 transmembrane glycoprotein . J Biomol Struct Dyn . 1997;15:465–471
- . Subdomain folding and biological activity of the core structure from human immunodeficiency virus type 1 gp41: implications for viral membrane fusion . J Virol . 1999;73:4433–4438
- Atomic structure of a thermostable subdomain of HIV-1 gp41 . Proc Natl Acad Sci USA . 1997;94:12303–12308
- Mode of action of an antiviral peptide from HIV-1. Inhibition at a post-lipid mixing stage . J Biol Chem . 2001;276:1391–1397
- C-terminal octylation rescues an inactive T20 mutant: implications for the mechanism of HIV/SIV-induced membrane fusion . J Biol Chem . 2003;278:21012–21017
- . Novel therapies based on mechanisms of HIV-1 cell entry . N Engl J Med . 2003;348:2228–2238
- Emergence of resistant human immunodeficiency virus type 1 in patients receiving fusion inhibitor (T-20) monotherapy . Antimicrob Agents Chemother . 2002;46:1896–1905
- Minimal variation in T-20 binding domain of different HIV-1 subtypes from antiretroviralnaive and -experienced patients . AIDS . 2002;16:1684–1686
- Rapid emergence of enfuvirtide resistance in HIV-1-infected patients: results of a clonal analysis . J Acquir Immune Defic Syndr . 2006;43:6–14
- Characterization of determinants of genotypic and phenotypic resistance to enfuvirtide in baseline and on-treatment HIV-1 isolates . AIDS . 2004;18:1787–1794
- The safety, plasma pharmacokinetics, and antiviral activity of subcutaneous enfuvirtide (T-20), a peptide inhibitor of gp41-mediated virus fusion, in HIV-infected adults . AIDS Res Hum Retroviruses . 2002;18:685–693
- Human immunodeficiency virus type 1 variants resistant to first- and secondversion fusion inhibitors and cytopathic in ex vivo human lymphoid tissue . J Virol . 2007;81:6563–6572
- Short-term safety and antiretroviral activity of T-1249, a second-generation fusion inhibitor of HIV . J Infect Dis . 2004;189:1075–1083
- Genotype and phenotype patterns of human immunodeficiency virus type 1 resistance to enfuvirtide during long-term treatment . Antimicrob Agents Chemother . 2004;48:3253–3259
- T-1249 retains potent antiretroviral activity in patients who had experienced virological failure while on an enfuvirtide-containing treatment regimen . J Infect Dis . 2005;191:1155–1163
- Evolution of Genotypic and Phenotypic Resistance during Chronic Treatment with the Fusion Inhibitor T-1249 . AIDS Res Hum retroviruses . 2007;23:1366–1373
- Delmedico M, Bray B, Cammack N, et al. Next generation HIV peptide fusion inhibitor candidates achieve potent, durable suppression of virus replication in vitro and improved pharmacokinetic properties. In: 13th Conference on Retroviruses and Opportunistic Infections, 2006;5–8 [Abstract].
- Design of helical, oligomeric HIV-1 fusion inhibitor peptides with potent activity against enfuvirtide-resistant virus . Proc Natl Acad Sci USA . 2007;104:12772–12777
- Design and evaluation of sifuvirtide, a novel HIV-1 fusion inhibitor . J Biol Chem . 2008;283:11126–11134
- FusoGen . Available at: http://www.fusogen.com [Date accessed: September 14, 2009]
- A synthetic peptide inhibitor of human immunodeficiency virus replication: correlation between solution structure and viral inhibition . Proc Natl Acad Sci USA . 1992;89:10537–10541
- Identification of a critical motif for the HIV-1 gp41 core structure: implication for designing novel anti-HIV fusion inhibitors . J Virol . 2008;82:6349–6358
- Potent HIV fusion inhibitors against Enfuvirtide-resistant HIV-1 strains . Proc Natl Acad Sci USA . 2008;105:16332–16337
- Remodeling of gp41-C34 peptide leads to highly effective inhibitors of the fusion of HIV-1 with target cells . Angew Chem Int Ed Engl . 2002;41:2937–2940
- Short constrained pep-tides that inhibit HIV-1 entry . Proc Natl Acad Sci USA . 2002;99:14664–14669
- . Crystal structure of GCN4-pIQI, a trimeric coiled coil with buried polar residues . J Mol Biol . 1998;284:859–865
- Inhibiting HIV-1 entry: discovery of D-peptide inhibitors that target the gp41 coiled-coil pocket . Cell . 1999;99:103–115
- Potent D-pep-tide inhibitors of HIV-1 entry . Proc Natl Acad Sci USA . 2007;104:16828–16833
- Protein design of a bacte-rially expressed HIV-1 gp41 fusion inhibitor . Biochemistry . 2007;46:4360–4369
- Protection of macaques from vaginal SHIV challenge by vaginally delivered inhibitors of virus-cell fusion . Nature . 2005;438:99–102
- . Rational design of highly potent HIV-1 fusion inhibitory proteins: implication for developing antiviral therapeutics . Biochem Biophys Res Commun . 2005;332:831–836
- Recombinant protein of heptad-repeat HR212, a stable fusion inhibitor with potent anti-HIV action in vitro . Virology . 2008;377:80–87
- Covalent trimers of the internal N-terminal trimeric coiled-coil of gp41 and antibodies directed against them are potent inhibitors of HIV envelope-mediated cell fusion . J Biol Chem . 2003;278:20278–20285
- . Protein design of an HIV-1 entry inhibitor . Science . 2001;291:884–888
- . Targeting therapeutics to an exposed and conserved binding element of the HIV-1 fusion protein . Proc Natl Acad Sci USA . 2003;100:5016–5021
- Discovery and optimization of a natural HIV-1 entry inhibitor targeting the gp41 fusion peptide . Cell . 2007;129:263–275
- . A conformation-specific monoclonal antibody reacting with fusion-active gp41 from the HIV-1 envelope glycoprotein . J Virol . 1998;72:10213–10217
- A screening assay for antiviral compounds targeted to the HIV-1 gp41 core structure using a conformation-specific monoclonal antibody . J Virol Methods . 1999;80:85–96
- . Structure-based identification of small molecule antiviral compounds targeted to the gp41 core structure of the human immunodecifiency virus type 1 . J Med Chem . 1999;42:3203–3209
- . A salt bridge between an N-terminal coiled coil of gp41 and an antiviral agent targeted to the gp41 core is important for anti-HIV-1 activity . Biochem Biophys Res Commun . 2000;270:153–157
- Conserved residue Lys574 in the cavity of HIV-1 gp41 coiled-coil domain is critical for six-helix bundle stability and virus entry . J Biol Chem . 2007;282:25631–25639
- Conserved salt-bridge between the N- and C-terminal heptad repeat regions of HIV-1 gp41 core structure is critical for virus entry and inhibition . J Virol . 2008;82:11129–11139
- 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 . 2004;48:4349–4359
- Design, synthesis, and biological evaluation of N-carboxyphenylpyrrole derivatives as potent HIV fusion inhibitors targeting gp41 . J Med Chem . 2008;51:7843–7854
- Design, synthesis, and structure-activity relationship of a novel series of 2-Aryl 5-(4-oxo-3-phenethyl-2-thioxothiazolidin-ylidenemethyl)furans as HIV-1 entry inhibitors . J Med Chem . 2009;52:7631–7639
- Selection of gp41-mediated HIV-1 cell entry inhibitors from biased combinatorial libraries of non-natural binding elements . Nat Struct Biol . 1999;6:953–960
- Design of a protein surface antagonist based on alpha-helix mimicry: inhibition of gp41 assembly and viral fusion . Angew Chem Int Ed Engl . 2002;41:278–281
- Evaluation of “credit card” libraries for inhibition of HIV-1 gp41 fusogenic core formation . J Comb Chem . 2006;8:531–539
- A fluorescence assay for rapid detection of ligand binding affinity to HIV-1 gp41 . Biol Chem . 2006;387:477–483
- . A novel fluorescence intensity screening assay identifies new low molecular weight inhibitors of the gp41 coiled coil domain of HIV-1 . Antimicrob Agents Chemother . 2007;51:2388–2395
- . Therapy of HIV infections: problems and prospects . Bull N Y Acad Med . 1996;73:37–45
- Human immunodeficiency virus type 1 entry inhibitors PRO 542 and T-20 are potently synergistic in blocking virus-cell and cell-cell fusion . J Infect Dis . 2001;183:1121–1125
- Strong in vitro synergy between the fusion inhibitor T-20 and the CXCR4 blocker AMD-3100 . J Acquir Immune Defic Syndr . 2000;25:99–102
- Anti-human immunodeficiency virus interactions of SCH-C (SCH 351125), a CCR5 antagonist, with other antiretroviral agents in vitro . Antimicrob Agents Chemother . 2002;46:1336–1339
- Synergistic efficacy of combination of enfuvirtide and sifuvirtide, the first- and next-generation HIV-fusion inhibitors . AIDS . 2009;23:639–641
- Combinations of the first and next generation HIV fusion inhibitors exhibit highly potent synergistic effect against enfuvirtide-sensitive and resistant HIV-1 strains . J Virol . 2009;83:7862–7872
- . Determinants of human immunodeficiency virus type 1 resistance to gp41-derived inhibitory peptides . J Virol . 1998;72:986–993
- Selection of T1249-resistant Human Immunodeficiency Virus type 1 variants . J Virol . 2008;82:6678–6688
- . Resistance to enfuvirtide, the first HIV fusion inhibitor . J Antimicrob Chemother . 2004;54:333–340
- Role of the envelope genetic context in the development of enfu-virtide resistance in human immunodeficiency virus type 1-infected patients . J Virol . 2006;80:8807–8819
- Enfuvirtide: the first therapy to inhibit the entry of HIV-1 into host CD4 lymphocytes . Nat Rev Drug Discov . 2004;3:215–225
- Impact of human immunodeficiency virus type 1 gp41 amino acid substitutions selected during enfuvirtide treatment on gp41 binding and antiviral potency of enfuvirtide in vitro . J Virol . 2005;79:12447–12454
- Clinical resistance to enfuvirtide does not affect susceptibility of human immunodeficiency virus type 1 to other classes of entry inhibitors . J Virol . 2007;81:3240–3250
- . HR-2 mutations in human immunodeficiency virus type 1 gp41 restore fusion kinetics delayed by HR-1 mutations that cause clinical resistance to enfuvirtide . J Virol . 2009;83:2989–2995
- The LLSGIV stretch of the N-terminal region of HIV-1 gp41 is critical for binding to a model peptide, T20 . Protein Eng . 2003;16:311–317
PII: S0929-6646(10)60029-0
doi:10.1016/S0929-6646(10)60029-0
© 2010 Formosan Medical Association & Elsevier. Published by Elsevier Inc. All rights reserved.
Volume 109, Issue 2 , Pages 94-105, February 2010
