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

• Tác giả: Masayuki Amano, Oksana Gerlits, Ajay K Ghosh, Arun K Ghosh, Megan Johnson, Andrey Kovalevsky, Hiroaki Mitsuya, Rangu Prasad, Ashish Sharma, Monika Yadav
• Ngôn ngữ: eng
• Ký hiệu phân loại: 624.1771 Structural engineering and underground construction
• Thông tin xuất bản: England : Bioorganic & medicinal chemistry letters , 2025
• Bộ sưu tập: NCBI
• ID: 690027

Tóm tắt

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.