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
  • 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: [email protected].
  • 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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