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Publication Abstract from PubMed

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.

Potent HIV‑1 protease inhibitors containing oxabicyclo octanol-derived P2-ligands: Design, synthesis, and X‑ray structural studies of inhibitor-HIV-1 protease complexes.,Ghosh AK, Yadav M, Sharma A, Johnson M, Ghosh AK, Prasad R, Amano M, Gerlits O, Kovalevsky A, Mitsuya H Bioorg Med Chem Lett. 2025 Jan 21;120:130109. doi: 10.1016/j.bmcl.2025.130109. PMID:39848476^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.