title: Betulinic acid derivatives that target gp120 and inhibit multiple genetic subtypes of human immunodeficiency virus type 1.
abstract: Betulinic acid (BA) derivatives can inhibit human immunodeficiency virus type 1 (HIV-1) entry or maturation depending on side chain modifications. While BA derivatives with antimaturation activity have attracted considerable interest, the anti-HIV-1 profile and molecular mechanism of BA derivatives with anti-HIV-1 entry activity (termed BA entry inhibitors) have not been well defined. In this study, we have found that two BA entry inhibitors, IC9564 and A43D, exhibited a broad spectrum of anti-HIV-1 activity. Both compounds inhibited multiple strains of HIV-1 from clades A, B, and C at submicromolar concentrations. Clade C viruses were more sensitive to the compounds than clade A and B viruses. Interestingly, IC9564 at subinhibitory concentrations could alter the antifusion activities of other entry inhibitors. IC9564 was especially potent in increasing the sensitivity of HIV-1 YU2 Env-mediated membrane fusion to the CCR5 inhibitor TAK-779. Results from this study suggest that the V3 loop of gp120 is a critical determinant for the anti-HIV-1 activity of IC9564. IC9564 escape viruses contained mutations near the tip of the V3 loop. Moreover, IC9564 could compete with the binding of V3 monoclonal antibodies 447-52D and 39F. IC9564 also competed with the binding of gp120/CD4 complexes to chemokine receptors. In summary, these results suggest that BA entry inhibitors can potently inhibit a broad spectrum of primary HIV-1 isolates by targeting the V3 loop of gp120.
authors.affiliation: Department of Surgery, Duke University Medical Center, Box 2826, Durham, NC 27710-2926, USA.
authors.forename: Weihong
authors.initials: W
authors.lastname: Lai
authors.forename: Li
authors.initials: L
authors.lastname: Huang
authors.forename: Phong
authors.initials: P
authors.lastname: Ho
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Li
authors.forename: David
authors.initials: D
authors.lastname: Montefiori
authors.forename: Chin-Ho
authors.initials: CH
authors.lastname: Chen
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology*; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D024882:Drug Resistance, Viral; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics; D023581:HIV Fusion Inhibitors / Q000737:chemistry / Q000494:pharmacology; D015497:HIV-1 / Q000145:classification* / Q000187:drug effects / Q000235:genetics / Q000472:pathogenicity; D006801:Humans; D008561:Membrane Fusion / Q000187:drug effects; D008826:Microbial Sensitivity Tests / Q000379:methods; D008958:Models, Molecular; D053978:Pentacyclic Triterpenes; D010446:Peptide Fragments / Q000737:chemistry / Q000187:drug effects; D014315:Triterpenes / Q000737:chemistry / Q000494:pharmacology*; D000094062:Betulinic Acid
chemical_list: D019380:Anti-HIV Agents; D015699:HIV Envelope Protein gp120; D023581:HIV Fusion Inhibitors; C059762:HIV envelope protein gp120 (305-321); C419364:IC9564; D053978:Pentacyclic Triterpenes; D010446:Peptide Fragments; D014315:Triterpenes; C514793:gp120 protein, Human immunodeficiency virus 1; D000094062:Betulinic Acid