Yang S S, Pattabiraman N, Gussio R, Pallansch L, Buckheit R W, Bader J P
Antiviral Evaluations Branch, NCI, Bethesda, MD, USA.
Leukemia. 1997 Apr;11 Suppl 3:89-92.
Oxathlin carboxanilide analogs (UC) and alpha APA, compounds recognized as nonnucleoside reverse transcriptase (RT) inhibitors (NNRTI), were evaluated for activity against the human immunodeficiency virus (HIV-1) and drug-resistant variants. These NNRTIs are structurally diverse but potent inhibitors of HIV-1 with efficacy in the nanomolar to low micromolar concentrations. They interact at a specific site in the pain domain of the p66 subunit of RT. Treatment of HIV-1 infected cell cultures with UC compounds resulted in the selection of drug-resistant viruses bearing specific amino acid changes at 100, 101, 103, 106, and/or 181. Since Y181C and L1001 are the most commonly observed resistance-engendering mutations, RT enzymatic analysis was correlated with molecular modeling to glean information on the structural interactions between these NNRTIs and RT. Information derived from these studies will facilitate rational drug design and the selection of complementary anti-HIV drugs for combination therapy.
恶嗪羧酰苯胺类似物（UC）和α-APA，这两种被认为是非核苷逆转录酶（RT）抑制剂（NNRTI）的化合物，针对人类免疫缺陷病毒（HIV-1）及其耐药变体的活性进行了评估。这些非核苷逆转录酶抑制剂结构多样，但却是HIV-1的强效抑制剂，在纳摩尔至低微摩尔浓度下具有疗效。它们在逆转录酶p66亚基的蛋白酶结构域的特定位点相互作用。用UC化合物处理HIV-1感染的细胞培养物导致选择出在100、101、103、106和/或181位点带有特定氨基酸变化的耐药病毒。由于Y181C和L100I是最常观察到的产生耐药性的突变，逆转录酶酶分析与分子建模相关联，以收集有关这些非核苷逆转录酶抑制剂与逆转录酶之间结构相互作用的信息。从这些研究中获得的信息将有助于合理的药物设计以及选择用于联合治疗的互补抗HIV药物。
