HIV Drug Resistance Program, National Cancer Institute, Frederick National Laboratory for Cancer Research, Frederick, MD 21702-1201, USA.
Retrovirology. 2012 Dec 5;9:99. doi: 10.1186/1742-4690-9-99.
The recently approved anti-AIDS drug rilpivirine (TMC278, Edurant) is a nonnucleoside inhibitor (NNRTI) that binds to reverse transcriptase (RT) and allosterically blocks the chemical step of DNA synthesis. In contrast to earlier NNRTIs, rilpivirine retains potency against well-characterized, clinically relevant RT mutants. Many structural analogues of rilpivirine are described in the patent literature, but detailed analyses of their antiviral activities have not been published. This work addresses the ability of several of these analogues to inhibit the replication of wild-type (WT) and drug-resistant HIV-1.
We used a combination of structure activity relationships and X-ray crystallography to examine NNRTIs that are structurally related to rilpivirine to determine their ability to inhibit WT RT and several clinically relevant RT mutants. Several analogues showed broad activity with only modest losses of potency when challenged with drug-resistant viruses. Structural analyses (crystallography or modeling) of several analogues whose potencies were reduced by RT mutations provide insight into why these compounds were less effective.
Subtle variations between compounds can lead to profound differences in their activities and resistance profiles. Compounds with larger substitutions replacing the pyrimidine and benzonitrile groups of rilpivirine, which reorient pocket residues, tend to lose more activity against the mutants we tested. These results provide a deeper understanding of how rilpivirine and related compounds interact with the NNRTI binding pocket and should facilitate development of novel inhibitors.
最近批准的抗艾滋病药物利匹韦林（TMC278，Edurant）是非核苷类抑制剂（NNRTI），它与逆转录酶（RT）结合，并变构抑制 DNA 合成的化学步骤。与早期的 NNRTIs 不同，利匹韦林对具有良好特征的、临床相关的 RT 突变体仍保持效力。利匹韦林的许多结构类似物在专利文献中有描述，但它们的抗病毒活性的详细分析尚未发表。这项工作研究了其中几种类似物抑制野生型（WT）和耐药性 HIV-1 复制的能力。
我们使用结构活性关系和 X 射线晶体学的组合，研究了与利匹韦林结构相关的 NNRTIs，以确定它们抑制 WT RT 和几种临床相关 RT 突变体的能力。几种类似物表现出广泛的活性，对耐药性病毒的效力只有适度的降低。对一些效力因 RT 突变而降低的类似物进行结构分析（晶体学或建模），提供了为什么这些化合物效果较差的见解。
化合物之间的细微差异会导致它们的活性和耐药性谱产生深远的差异。用取代嘧啶和苯甲腈基团的较大取代基替换利匹韦林的化合物，会重新定向口袋残基，往往会对我们测试的突变体失去更多的活性。这些结果提供了对利匹韦林和相关化合物与 NNRTI 结合口袋相互作用的更深入理解，应有助于开发新型抑制剂。
