Bioinformatics Institute, A*STAR, 30 Biopolis Street, #07-01 Matrix, Singapore 138671, Singapore.
Experimental Drug Development Centre, A*STAR, 10 Biopolis Road Chromos #05-01, Singapore 138670, Singapore.
Molecules. 2020 Dec 13;25(24):5902. doi: 10.3390/molecules25245902.
The ongoing development of drug resistance in HIV continues to push for the need of alternative drug targets in inhibiting HIV. One such target is the Reverse transcriptase (RT) enzyme which is unique and critical in the viral life cycle-a rational target that is likely to have less off-target effects in humans. Serendipitously, we found two chemical scaffolds from the National Cancer Institute (NCI) Diversity Set V that inhibited HIV-1 RT catalytic activity. Computational structural analyses and subsequent experimental testing demonstrated that one of the two chemical scaffolds binds to a novel location in the HIV-1 RT p51 subunit, interacting with residue Y183, which has no known association with previously reported drug resistance. This finding supports the possibility of a novel druggable site on p51 for a new class of non-nucleoside RT inhibitors that may inhibit HIV-1 RT allosterically. Although inhibitory activity was shown experimentally to only be in the micromolar range, the scaffolds serve as a proof-of-concept of targeting the HIV RT p51 subunit, with the possibility of medical chemistry methods being applied to improve inhibitory activity towards more effective drugs.
HIV 耐药性的持续发展继续推动着寻找抑制 HIV 的替代药物靶点的需求。逆转录酶 (RT) 是一个独特且关键的病毒生命周期靶点，作为一个合理的靶点，它在人类中可能具有较少的脱靶效应。我们偶然发现来自国家癌症研究所 (NCI) 多样性集 V 的两种化学支架可抑制 HIV-1 RT 催化活性。计算结构分析和随后的实验测试表明，这两种化学支架中的一种结合到 HIV-1 RT p51 亚基的一个新位置，与残基 Y183 相互作用，该残基与以前报道的耐药性没有已知关联。这一发现支持了 p51 上存在新的可成药位点的可能性，用于一类可能变构抑制 HIV-1 RT 的新型非核苷 RT 抑制剂。尽管实验显示抑制活性仅在微摩尔范围内，但这些支架可作为针对 HIV RT p51 亚基的概念验证，有可能应用医学化学方法来提高对更有效药物的抑制活性。
