Akther Thamina, McFadden William M, Zhang Huanchun, Kirby Karen A, Sarafianos Stefan G, Wang Zhengqiang
Center for Drug Design, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA.
Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Children's Healthcare of Atlanta, Atlanta, GA 30322, USA.
Med Chem Res. 2024 Dec;33(12):2431-2447. doi: 10.1007/s00044-024-03305-0. Epub 2024 Sep 15.
The recent FDA-approval of lenacapavir (LEN, GS-6207) and the subsequent discovery of GSK878 strongly validate HIV-1 capsid protein (CA) as a target for antiviral development. However, multiple single mutations drastically reduced the susceptibility of HIV-1 to both GS-6207 and GSK878, necessitating the design and synthesis of novel sub-chemotypes. With the aid of induced-fit molecular docking, we have designed a few new hybrids combining the quinazolinone scaffold of GSK878 and an N-terminal cap from other CA-targeting chemotypes. We have also worked out a modular synthesis of these novel subtypes. Although these new analogs only weakly inhibited HIV-1 and produced relatively small shifts in the thermal shift assay against pre-assembled CA hexamers, the design and synthesis reported herein inform future design and synthesis of structurally more elaborate analogs for improved potency.
近期美国食品药品监督管理局（FDA）批准了来那卡帕韦（LEN，GS - 6207），随后又发现了GSK878，这有力地证实了HIV - 1衣壳蛋白（CA）是抗病毒药物研发的一个靶点。然而，多个单点突变极大地降低了HIV - 1对GS - 6207和GSK878的敏感性，因此需要设计和合成新型的亚化学型。借助诱导契合分子对接技术，我们设计了一些新的杂合物，将GSK878的喹唑啉酮骨架与其他靶向CA的化学型的N端帽相结合。我们还研究出了这些新型亚型的模块化合成方法。尽管这些新类似物对HIV - 1的抑制作用较弱，并且在针对预组装CA六聚体的热位移测定中产生的位移相对较小，但本文报道的设计和合成方法为未来设计和合成结构更精细、效力更高的类似物提供了参考。
