Design and Evaluation of Novel HIV-1 Protease Inhibitors Containing Phenols or Polyphenols as P2 Ligands with High Activity against DRV-Resistant HIV-1 Variants.
Design and Evaluation of Novel HIV-1 Protease Inhibitors Containing Phenols or Polyphenols as P2 Ligands with High Activity against DRV-Resistant HIV-1 Variants.
复制标题
含有酚或多酚作为 P2 配体的新型 HIV-1 蛋白酶抑制剂的设计和评估，对 DRV 耐药 HIV-1 变异体具有高活性
DOI：
10.3390/ijms232214178
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发表时间：
2022-11-16
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
--
作者：
随着耐药变异的日益流行，迫切需要具有广谱抗病毒活性的新型强效HIV-1蛋白酶抑制剂来对抗多药耐药致病病毒。在此，我们设计并合成了一系列新的HIV-1蛋白酶抑制剂，以酚类或多酚类作为P2配体，以多种磺胺类似物作为P2 '配体。这些新的抑制剂显示出极好的酶抑制活性和抗病毒活性。特别是，抑制剂15d和15f在低皮摩尔范围内表现出有效的酶抑制活性，后者对耐darunvir的HIV-1变体表现出出色的活性。此外，分子模型研究提供了抑制剂与酶腔之间配体结合位点相互作用的见解，并为进一步优化强效抑制剂提供了灵感。
With the increasing prevalence of drug-resistant variants, novel potent HIV-1 protease inhibitors with broad-spectrum antiviral activity against multidrug-resistant causative viruses are urgently needed. Herein, we designed and synthesized a new series of HIV-1 protease inhibitors with phenols or polyphenols as the P2 ligands and a variety of sulfonamide analogs as the P2′ ligands. A number of these new inhibitors showed superb enzymatic inhibitory activity and antiviral activity. In particular, inhibitors 15d and 15f exhibited potent enzymatic inhibitory activity in the low picomolar range, and the latter showed excellent activity against the Darunavir-resistant HIV-1 variant. Furthermore, the molecular modeling studies provided insight into the ligand-binding site interactions between inhibitors and the enzyme cavity, and they sparked inspiration for the further optimization of potent inhibitors.
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影响因子：
7.3
作者：
Ghosh AK;Williams JN;Ho RY;Simpson HM;Hattori SI;Hayashi H;Agniswamy J;Wang YF;Weber IT;Mitsuya H
通讯作者：
Mitsuya H
影响因子：
6.4
作者：
Aoki M;Das D;Hayashi H;Aoki-Ogata H;Takamatsu Y;Ghosh AK;Mitsuya H
通讯作者：
Mitsuya H
影响因子：
7.3
作者：
Ghosh AK;Osswald HL;Prato G
通讯作者：
Prato G
影响因子：
14.9
作者：
Cer RZ;Mudunuri U;Stephens R;Lebeda FJ
通讯作者：
Lebeda FJ
影响因子：
3.6
作者：
Ghosh, AK;Leshchenko, S;Noetzel, M
通讯作者：
Noetzel, M