title: New betulinic acid derivatives for bevirimat-resistant human immunodeficiency virus type-1.
abstract: Bevirimat (1, BVM) is an anti-HIV agent that blocks HIV-1 replication by interfering with HIV-1 Gag-SP1 processing at a late stage of viral maturation. However, clinical trials of 1 have revealed a high baseline drug resistance that is attributed to naturally occurring polymorphisms in HIV-1 Gag. To overcome the drug resistance, 28 new derivatives of 1 were synthesized and tested against compound 1-resistant (BVM-R) HIV-1 variants. Among them, compound 6 exhibited much improved activity against several HIV-1 strains carrying BVM-R polymorphisms. Compound 6 was at least 20-fold more potent than 1 against the replication of NL4-3/V370A, which carries the most prevalent clinical BVM-R polymorphism in HIV-1 Gag-SP1. Thus, compound 6 merits further development as a potential anti-AIDS clinical trial candidate.
authors: Surgical Science, Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, United States.
authors: Zhao
authors: Z
authors: Dang
authors: Phong
authors: P
authors: Ho
authors: Lei
authors: L
authors: Zhu
authors: Keduo
authors: K
authors: Qian
authors: Kuo-Hsiung
authors: KH
authors: Lee
authors: Li
authors: L
authors: Huang
authors: Chin-Ho
authors: CH
authors: Chen
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy*; D019380:Anti-HIV Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002460:Cell Line; D024882:Drug Resistance, Viral; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D011110:Polymorphism, Genetic; D013386:Succinates / Q000627:therapeutic use*; D014315:Triterpenes / Q000138:chemical synthesis / Q000627:therapeutic use*; D014779:Virus Replication / Q000187:drug effects; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000235:genetics*; D000094062:Betulinic Acid; D053978:Pentacyclic Triterpenes
chemical_list: D019380:Anti-HIV Agents; D013386:Succinates; D014315:Triterpenes; D054301:gag Gene Products, Human Immunodeficiency Virus; C581005:methyl N-(N'-(3-O-(3',3'-dimethylsuccinyl)betulinic acid-28-oyl)-9-aminononanoyl)glutaminate; D000094062:Betulinic Acid; C479935:bevirimat; D053978:Pentacyclic Triterpenes
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