New Betulinic Acid Derivatives for Bevirimat-Resistant Human Immunodeficiency Virus Type‑1

• Published in: Journal of medicinal chemistry Vol. 56; no. 5; pp. 2029 - 2037
• Main Authors: Dang, Zhao, Ho, Phong, Zhu, Lei, Qian, Keduo, Lee, Kuo-Hsiung, Huang, Li, Chen, Chin-Ho
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 14.03.2013; Amer Chemical Soc
• Subjects: Acquired Immunodeficiency Syndrome - drug therapy; Anti-HIV Agents - pharmacology; Anti-HIV Agents - therapeutic use; Cell Line; Chemistry, Medicinal; Drug Resistance, Viral; gag Gene Products, Human Immunodeficiency Virus - genetics; HIV-1 - drug effects; HIV-1 - genetics; Humans; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Polymorphism, Genetic; Science & Technology; Succinates - therapeutic use; Triterpenes - chemical synthesis; Triterpenes - therapeutic use; Virus Replication - drug effects; POLYMORPHISMS; REPLICATION; ENTRY; ANALOGS; SAFETY; ANTI-HIV; STEP; HIV-1 MATURATION INHIBITOR
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/jm3016969

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.