2. Academic Validation
  3. Structure-based design of potent HIV-1 protease inhibitors with modified P1-biphenyl ligands: synthesis, biological evaluation, and enzyme-inhibitor X-ray structural studies

Structure-based design of potent HIV-1 protease inhibitors with modified P1-biphenyl ligands: synthesis, biological evaluation, and enzyme-inhibitor X-ray structural studies

  • J Med Chem. 2015 Jul 9;58(13):5334-43. doi: 10.1021/acs.jmedchem.5b00676.
Arun K Ghosh 1,  Xufen Yu 1,  Heather L Osswald 1,  Johnson Agniswamy 2,  Yuan-Fang Wang 2,  Masayuki Amano 3,  Irene T Weber 2,  Hiroaki Mitsuya 3 4 5
Affiliations

Affiliations

  • 1 †Departments of Chemistry and Medicinal Chemistry, Purdue University, 560 Oval Drive, 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 Hematology and Infectious Diseases, Kumamoto University Graduate School of Medical and Pharmaceutical Sciences, Kumamoto 860-8556, Japan.
  • 4 ∥Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, United States.
  • 5 ⊥Center for Clinical Sciences, National Center for Global Health and Medicine, Tokyo 162-8655, Japan.
PMID: 26107245 DOI: 10.1021/acs.jmedchem.5b00676
Abstract

We report the design, synthesis, X-ray structural studies, and biological evaluation of a novel series of HIV-1 Protease Inhibitors. We designed a variety of functionalized biphenyl derivatives to make enhanced van der Waals interactions in the S1 subsite of HIV-1 protease. These biphenyl derivatives were conveniently synthesized using a Suzuki-Miyaura cross-coupling reaction as the key step. We examined the potential of these functionalized biphenyl-derived P1 ligands in combination with 3-(S)-tetrahydrofuranyl urethane and bis-tetrahydrofuranyl urethane as the P2 ligands. Inhibitor 21e, with a 2-methoxy-1,1'-biphenyl derivative as P1 ligand and bis-THF as the P2 ligand, displayed the most potent Enzyme inhibitory and Antiviral activity. This inhibitor also exhibited potent activity against a panel of multidrug-resistant HIV-1 variants. A high resolution X-ray crystal structure of related Boc-derivative 17a-bound HIV-1 protease provided important molecular insight into the ligand-binding site interactions of the biphenyl core in the S1 subsite of HIV-1 protease.

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