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

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number130109
JournalBioorganic and Medicinal Chemistry Letters
Volume120
DOIs
StatePublished - May 1 2025

Keywords

  • Cyclic ligands
  • Cycloaddition
  • HIV-1 protease
  • Inhibitor
  • X-ray structure

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