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

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

  • Bioorg Med Chem Lett. 2025 Jan 21:120:130109. doi: 10.1016/j.bmcl.2025.130109.
Arun K Ghosh 1,  Monika Yadav 2,  Ashish Sharma 2,  Megan Johnson 2,  Ajay K Ghosh 2,  Rangu Prasad 2,  Masayuki Amano 3,  Oksana Gerlits 4,  Andrey Kovalevsky 5,  Hiroaki Mitsuya 6
Affiliations

Affiliations

  • 1 Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA; Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA. Electronic address: akghosh@purdue.edu.
  • 2 Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA.
  • 3 Department of Infectious Diseases, Kumamoto University School of Medicine, Kumamoto 860-8556, Japan.
  • 4 Department of Natural Sciences, Tennessee Wesleyan University, Athens, TN 37303, USA.
  • 5 Neutron Scattering Division, Oak Ridge National Laboratory, 1 Bethel Valley Road, Oak Ridge, TN 37831, USA.
  • 6 Department of Infectious Diseases, Kumamoto University School of Medicine, Kumamoto 860-8556, Japan; Department of Refractory Infectious Diseases, National Center for Global Health and Medicine Research Institute, Tokyo 162-8655, Japan; Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
PMID: 39848476 DOI: 10.1016/j.bmcl.2025.130109
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.

Keywords

Cyclic ligands; Cycloaddition; HIV-1 protease; Inhibitor; X-ray structure.

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