Department of Chemistry, University of South Alabama, Mobile, AL 36688, USA.
Department of Chemistry and Biochemistry, University of Southern Mississippi, Hattiesburg, MS 39406, USA.
Viruses. 2022 Jul 2;14(7):1466. doi: 10.3390/v14071466.
Allosteric HIV-1 integrase (IN) inhibitors, or ALLINIs, are a new class of antiviral agents that bind at the dimer interface of the IN, away from the enzymatic catalytic site and block viral replication by triggering an aberrant multimerization of the viral enzyme. To further our understanding of the important binding features of multi-substituted quinoline-based ALLINIs, we have examined the IN multimerization and antiviral properties of substitution patterns at the 6 or 8 position. We found that the binding properties of these ALLINIs are negatively impacted by the presence of bulky substitutions at these positions. In addition, we have observed that the addition of bromine at either the 6 (6-bromo) or 8 (8-bromo) position conferred better antiviral properties. Finally, we found a significant loss of potency with the 6-bromo when tested with the ALLINI-resistant IN A128T mutant virus, while the 8-bromo analog retained full effectiveness.
变构 HIV-1 整合酶（IN）抑制剂，或 ALLINIs，是一类新型抗病毒药物，它们结合在 IN 的二聚体界面上，远离酶的催化位点，并通过触发病毒酶的异常多聚化来阻断病毒复制。为了进一步了解基于多取代喹啉的 ALLINIs 的重要结合特征，我们研究了 6 位或 8 位取代模式的 IN 多聚化和抗病毒特性。我们发现，这些 ALLINIs 的结合特性因这些位置存在大取代基而受到负面影响。此外，我们观察到在 6 位（6-溴）或 8 位（8-溴）添加溴可赋予更好的抗病毒特性。最后，我们发现当用具有抗 ALLINI 的 IN A128T 突变病毒进行测试时，6-溴的效力显著丧失，而 8-溴类似物则保持完全有效。
