Pu Jing, Dai Yu, Wang Qian, Lu Lu, Zhang Junqi, Xu Wei, Xie Lan, Wang Shengqi, Yu Fei, He Xiaoyang, Jiang Shibo
Key Laboratory of Medical Molecular Virology of MOE/MOH, School of Basic Medical Sciences & Shanghai Public Health Clinical Center, Fudan University, Shanghai, China.
Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY, United States.
Front Pharmacol. 2021 Jan 25;11:613361. doi: 10.3389/fphar.2020.613361. eCollection 2020.
Virus inactivator can inactivate cell-free virions without relying on their replication cycle, potentially reducing the impact of viral infection on cells. Previously, we successfully constructed a HIV-1 protein inactivator, 2DLT, by conjugating the D1D2 region of CD4 to the fusion inhibitor T1144 via a 35-amino acid linker. Therefore, it targets both the CD4 binding site in gp120 and NHR region in gp41. Considering that small-molecule agents have the advantages of fast production, low cost, good stability, and oral availability, we herein report the design of a new small-molecule HIV-1 inactivator, FD028, by conjugating FD016 (an analog of NBD-556, a gp120-CD4 binding inhibitor) with FD017 (an analog of 11d, an HIV-1 fusion inhibitor). The results showed that FD028 inactivated cell-free virions at a moderate nanomolar concentration by targeting both HIV-1 gp120 and gp41. Moreover, FD028 has broad-spectrum inhibition and inactivation activity against HIV-1 resistant strains and primary isolates of different subtypes without significant cytotoxicity. Therefore, FD028 has potential for further development as an HIV-1 inactivator-based therapeutic.
病毒灭活剂可以在不依赖病毒复制周期的情况下灭活游离病毒粒子，从而有可能降低病毒感染对细胞的影响。此前，我们通过一个35个氨基酸的连接子将CD4的D1D2区域与融合抑制剂T1144偶联，成功构建了一种HIV-1蛋白灭活剂2DLT。因此，它同时靶向gp120中的CD4结合位点和gp41中的NHR区域。鉴于小分子药物具有生产速度快、成本低、稳定性好和口服可用性等优点，我们在此报告一种新型小分子HIV-1灭活剂FD028的设计，该灭活剂通过将FD016（NBD-556的类似物，一种gp120-CD4结合抑制剂）与FD017（11d的类似物，一种HIV-1融合抑制剂）偶联而成。结果表明，FD028通过靶向HIV-1的gp120和gp41，在中等纳摩尔浓度下灭活游离病毒粒子。此外，FD028对HIV-1耐药菌株和不同亚型的原代分离株具有广谱抑制和灭活活性，且无明显细胞毒性。因此，FD028作为一种基于HIV-1灭活剂的治疗药物具有进一步开发的潜力。
