Potent HIV‑1 protease inhibitors containing oxabicyclo octanol-derived P2-ligands: Design, synthesis, and X‑ray structural studies of inhibitor-HIV-1 protease complexes

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-01-21 DOI:10.1016/j.bmcl.2025.130109

Arun K. Ghosh , Monika Yadav , Ashish Sharma , Megan Johnson , Ajay K. Ghosh , Rangu Prasad , Masayuki Amano , Oksana Gerlits , Andrey Kovalevsky , Hiroaki Mitsuya

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Abstract

We describe here the design, synthesis, and X-ray structural studies of a new class of HIV-1 protease inhibitors containing 8-oxabicyclo[3.2.1]octanol-derived P2 ligands. We investigated the functional effect of these stereochemically defined fused-poly cyclic ligands on enzyme inhibition and antiviral activity in MT-2 cells. The tricyclic core of 8-oxabicyclo[3.2.1]octan-6-ol is designed to interact with the residues in the S2 subsite of HIV-1 protease. The syntheses of the ligands were carried out using the [5+2]-cycloaddition as the key step. Several inhibitors exhibited potent enzyme inhibitory activity. High resolution room-temperature X-ray structures of inhibitor-bound HIV-1 protease were determined. These structures provided important molecular insights for further design and optimization of inhibitor potency.

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含有恶沙比环辛醇衍生的p2配体的强效HIV-1蛋白酶抑制剂：抑制剂HIV-1蛋白酶复合物的设计、合成和X射线结构研究

我们在这里描述了一类含有8-氧沙环[3.2.1]辛醇衍生P2配体的新型HIV-1蛋白酶抑制剂的设计、合成和x射线结构研究。我们研究了这些立体化学定义的融合多环配体对MT-2细胞酶抑制和抗病毒活性的功能影响。8-恶沙环[3.2.1]辛烷-6-醇的三环核心被设计用于与HIV-1蛋白酶S2亚位中的残基相互作用。以[5+2]-环加成为关键步骤进行了配体的合成。几种抑制剂表现出有效的酶抑制活性。高分辨率室温x射线结构的抑制剂结合HIV-1蛋白酶测定。这些结构为进一步设计和优化抑制剂效力提供了重要的分子见解。

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来源期刊

Bioorganic & Medicinal Chemistry Letters 医学-医药化学

CiteScore

5.70

自引率

3.70%

发文量

463

审稿时长

27 days

期刊介绍： Bioorganic & Medicinal Chemistry Letters presents preliminary experimental or theoretical research results of outstanding significance and timeliness on all aspects of science at the interface of chemistry and biology and on major advances in drug design and development. The journal publishes articles in the form of communications reporting experimental or theoretical results of special interest, and strives to provide maximum dissemination to a large, international audience.