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, Arun K.; Yadav, Monika; Sharma, Ashish; Johnson, Megan; Ghosh, Ajay K.; Prasad, Rangu; Amano, Masayuki; Gerlits, Oksana; Kovalevskyi, Andrii Y.; Mitsuya, Hiroaki

doi:10.1016/j.bmcl.2025.130109

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

Journal Article · 21 January 2025 · Bioorganic and Medicinal Chemistry Letters

DOI: https://doi.org/10.1016/j.bmcl.2025.130109 · OSTI ID:2538119

Ghosh, Arun K. ^[1]; Yadav, Monika ^[1]; Sharma, Ashish ^[1]; Johnson, Megan ^[1]; Ghosh, Ajay K. ^[1]; Prasad, Rangu ^[1]; Amano, Masayuki ^[2]; Gerlits, Oksana ^[3];

^[4]; Mitsuya, Hiroaki ^[5]

Purdue Univ., West Lafayette, IN (United States)
Kumamoto University (Japan)
Tennessee Wesleyan Univ., Athens, TN (United States)
Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)
Kumamoto University (Japan); National Center for Global Health and Medicine Research Institute, Tokyo (Japan); National Institutes of Health (NIH), Bethesda, MD (United States)

Here, 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.

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Research Organization:: Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities (SUF)

Grant/Contract Number:: AC05-00OR22725

OSTI ID:: 2538119

Journal Information:: Bioorganic and Medicinal Chemistry Letters, Journal Name: Bioorganic and Medicinal Chemistry Letters Vol. 120; ISSN 0960-894X

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

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60 APPLIED LIFE SCIENCES
Cyclic ligands
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Inhibitor
X-ray structure

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

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