期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 56, 期 5, 页码 2029-2037出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm3016969
关键词
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资金
- National Institute of Allergy and Infectious Diseases (NIAID) grant [AI-65310]
- NIAID [AI-077417, AI-033066]
- D. P. Bolognesi Award, Duke University Medical Center
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.
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