New betulinic acid derivatives for bevirimat-resistant human immunodeficiency virus type-1.
New betulinic acid derivatives for bevirimat-resistant human immunodeficiency virus type-1.
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DOI：
10.1021/jm3016969
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发表时间：
2013-03-14
影响因子：
7.3
通讯作者：
Chen, Chin-Ho
中科院分区：
文献类型：
--
作者：
Dang, Zhao;Ho, Phong;Zhu, Lei;Qian, Keduo;Lee, Kuo-Hsiung;Huang, Li;Chen, Chin-Ho
Bevirimat（1，BVM）是一种抗HIV药物，通过在病毒成熟后期干扰HIV-1 Gag-SP1加工来阻断HIV-1复制。然而，1例的临床试验揭示了高基线耐药性，这归因于HIV-1 Gag中天然存在的多态性。为了克服耐药性，合成了28种1的新衍生物，并针对化合物1抗性（BVM-R）HIV-1变体进行了测试。其中，化合物6对几种携带BVM-R多态性的HIV-1株表现出显著提高的活性。化合物6针对NL 4 -3/V370 A的复制的效力比1强至少20倍，NL 4 -3/V370 A携带HIV-1 Gag-SP1中最普遍的临床BVM-R多态性。因此，化合物6值得进一步开发作为潜在的抗艾滋病临床试验候选者。
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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