Dept. of Biotechnology and Bioinformatics, School of Life Sciences, University of Hyderabad, India.
School of Chemistry, University of Hyderabad, Hyderabad 500046, India.
Bioorg Chem. 2021 Nov;116:105313. doi: 10.1016/j.bioorg.2021.105313. Epub 2021 Aug 30.
The third variable loop region (V3 loop) on gp120 plays an important role in cellular entry of HIV-1. Its interaction with the cellular CD4 and coreceptors is an important hallmark in facilitating the bridging by gp41 and subsequent fusion of membranes for transfer of viral genetic material. Further, the virus phenotype determines the cell tropism via respective co- receptor binding. Thus, coreceptor binding motif of envelope is considered to be a potent anti-viral drug target for viral entry inhibition. However, its high variability in sequence is the major hurdle for developing inhibitors targeting the region. In this study, we have used an in silico Virtual Screening and "Fragment-based" method to design small molecules based on the gp120 V3 loop interactions with a potent broadly neutralizing human monoclonal antibody, 447-52D. From the in silico analysis a potent scaffold, 1,3,5-triazine was identified for further development. Derivatives of 1,3,5-triazine with specific functional groups were designed and synthesized keeping the interaction with co-receptor intact. Finally, preliminary evaluation of molecules for HIV-1 inhibition on two different virus strains (clade C, clade B) yielded IC50 < 5.0 μM. The approach used to design molecules based on broadly neutralizing antibody, was useful for development of target specific potent antiviral agents to prevent HIV entry. The study reported promising inhibitors that could be further developed and studied.
HIV-1 病毒的 gp120 上的第三个可变环区（V3 环）在细胞进入中起着重要作用。它与细胞 CD4 和辅助受体的相互作用是促进 gp41 桥接以及随后膜融合以转移病毒遗传物质的重要标志。此外，病毒表型通过各自的共受体结合决定细胞嗜性。因此，包膜的共受体结合基序被认为是抑制病毒进入的有效抗病毒药物靶标。然而，其序列的高度变异性是开发针对该区域的抑制剂的主要障碍。在这项研究中，我们使用了一种基于 gp120 V3 环与一种有效的广谱中和人单克隆抗体 447-52D 相互作用的计算虚拟筛选和“基于片段”方法来设计小分子。通过计算机分析，确定了一种有潜力的支架 1,3,5-三嗪，用于进一步开发。设计了具有特定功能基团的 1,3,5-三嗪衍生物，以保持与辅助受体的相互作用完整。最后，对两种不同病毒株（C 型、B 型）的 HIV-1 抑制分子进行初步评估，得到 IC50<5.0 μM。基于广谱中和抗体设计分子的方法对于开发针对特定靶点的有效抗病毒药物以预防 HIV 进入是有用的。该研究报告了有前途的抑制剂，可进一步开发和研究。
