Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China.
Key Laboratory of the Ministry of Education for Advanced Catalysis Materials, Department of Chemistry, Zhejiang Normal University, Jinhua, 321004, China.
Eur J Med Chem. 2021 Aug 5;220:113450. doi: 10.1016/j.ejmech.2021.113450. Epub 2021 Apr 20.
A novel class of HIV-1 protease inhibitors with flexible piperidine as the P2 ligand was designed with the aim of improving extensive interactions with the active subsites. Many inhibitors exhibited good to excellent inhibitory effect on enzymatic activity and viral infectivity. In particular, inhibitor 3a with (R)-piperidine-3-carboxamide as the P2 ligand and 4-methoxybenzenesulfonamide as the P2' ligand showed an enzyme K value of 29 pM and antiviral IC value of 0.13 nM, more than six-fold enhancement of activity compared to DRV. Furthermore, there was no significant change in potency against DRV-resistant mutations and HIV-1 variant for 3a. Besides, inhibitor 3a exhibited potent antiviral activity against subtype C variants with low nanomole EC values. In addition, the molecular modeling revealed important hydrogen bonds and other favorable van der Waals interactions with the backbone atoms of the protease and provided insight for designing and optimizing more potent HIV-1 protease inhibitors.
设计了一类新型的 HIV-1 蛋白酶抑制剂，以灵活的哌啶作为 P2 配体，旨在增强与活性部位的广泛相互作用。许多抑制剂对酶活性和病毒感染力表现出良好到优异的抑制作用。特别是，抑制剂 3a 以（R）-哌啶-3-甲酰胺作为 P2 配体和 4-甲氧基苯磺酰胺作为 P2' 配体，其酶 K 值为 29 pM，抗病毒 IC 值为 0.13 nM，与 DRV 相比，活性提高了六倍以上。此外，3a 对 DRV 耐药突变和 HIV-1 变异体的效力没有明显变化。此外，抑制剂 3a 对低纳摩尔 EC 值的 C 型亚型变体表现出强大的抗病毒活性。此外，分子建模揭示了与蛋白酶主链原子的重要氢键和其他有利的范德华相互作用，为设计和优化更有效的 HIV-1 蛋白酶抑制剂提供了深入了解。
