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Title: Highly Potent HIV-1 Protease Inhibitors with Novel Tricyclic P2 Ligands: Design, Synthesis, and Protein-Ligand X-ray Studies

The design, synthesis, and biological evaluation of a series of HIV-1 protease inhibitors incorporating stereochemically defined fused tricyclic P2 ligands are described. Various substituent effects were investigated to maximize the ligand-binding site interactions in the protease active site. Inhibitors 16a and 16f showed excellent enzyme inhibitory and antiviral activity, although the incorporation of sulfone functionality resulted in a decrease in potency. Both inhibitors 16a and 16f maintained activity against a panel of multidrug resistant HIV-1 variants. A high-resolution X-ray crystal structure of 16a-bound HIV-1 protease revealed important molecular insights into the ligand-binding site interactions, which may account for the inhibitor’s potent antiviral activity and excellent resistance profiles.
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Publication Date:
OSTI Identifier:
Resource Type:
Journal Article
Resource Relation:
Journal Name: Journal of Medicinal Chemistry; Journal Volume: 56; Journal Issue: (17) ; 09, 2013
American Chemical Society (ACS)
Research Org:
Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
Sponsoring Org:
Country of Publication:
United States