2. Academic Validation
  3. Design of HIV-1 Protease Inhibitors with Amino-bis-tetrahydrofuran Derivatives as P2-Ligands to Enhance Backbone-Binding Interactions: Synthesis, Biological Evaluation, and Protein-Ligand X-ray Studies

Design of HIV-1 Protease Inhibitors with Amino-bis-tetrahydrofuran Derivatives as P2-Ligands to Enhance Backbone-Binding Interactions: Synthesis, Biological Evaluation, and Protein-Ligand X-ray Studies

  • J Med Chem. 2015 Sep 10;58(17):6994-7006. doi: 10.1021/acs.jmedchem.5b00900.
Arun K Ghosh 1,  Cuthbert D Martyr 1,  Heather L Osswald 1,  Venkat Reddy Sheri 1,  Luke A Kassekert 1,  Shujing Chen 1,  Johnson Agniswamy 2,  Yuan-Fang Wang 2,  Hironori Hayashi 3 4,  Manabu Aoki 3 5 6,  Irene T Weber 2,  Hiroaki Mitsuya 3 4 6
Affiliations

Affiliations

  • 1 Department of Chemistry and Department of Medicinal Chemistry, Purdue University , West Lafayette, Indiana 47907, United States.
  • 2 Department of Biology, Molecular Basis of Disease, Georgia State University , Atlanta, Georgia 30303, United States.
  • 3 Departments of Infectious Diseases and Hematology, Kumamoto University Graduate School of Biomedical Sciences , Kumamoto 860-8556, Japan.
  • 4 Center for Clinical Sciences, National Center for Global Health and Medicine , Tokyo 162-8655, Japan.
  • 5 Department of Medical Technology, Kumamoto Health Science University , Kumamoto 861-5598, Japan.
  • 6 Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health , Bethesda, Maryland 20892, United States.
PMID: 26306007 DOI: 10.1021/acs.jmedchem.5b00900
Abstract

Structure-based design, synthesis, and biological evaluation of a series of very potent HIV-1 Protease Inhibitors are described. In an effort to improve backbone ligand-binding site interactions, we have incorporated basic-amines at the C4 position of the bis-tetrahydrofuran (bis-THF) ring. We speculated that these substituents would make hydrogen bonding interactions in the FLAP region of HIV-1 protease. Synthesis of these inhibitors was performed diastereoselectively. A number of inhibitors displayed very potent Enzyme inhibitory and Antiviral activity. Inhibitors 25f, 25i, and 25j were evaluated against a number of highly-PI-resistant HIV-1 strains, and they exhibited improved Antiviral activity over darunavir. Two high resolution X-ray structures of 25f- and 25g-bound HIV-1 protease revealed unique hydrogen bonding interactions with the backbone carbonyl group of Gly48 as well as with the backbone NH of Gly48 in the FLAP region of the Enzyme active site. These ligand-binding site interactions are possibly responsible for their potent activity.

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