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Title: 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

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.

Authors:
 [1];  [1];  [1];  [1];  [1];  [1];  [2];  [2];  [3];  [4];  [2];  [3]
  1. Purdue Univ., West Lafayette, IN (United States)
  2. Georgia State Univ., Atlanta, GA (United States)
  3. Kumamoto Univ. (Japan); National Center for Global Health and Medicine, Tokyo (Japan)
  4. Kumamoto Health Science Univ. (Japan)
Publication Date:
Research Org.:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE
OSTI Identifier:
1222022
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
J. Med. Chem.
Additional Journal Information:
Journal Volume: 58; Journal Issue: 17
Country of Publication:
United States
Language:
ENGLISH

Citation Formats

Ghosh, Arun K., Martyr, Cuthbert D., Osswald, Heather L., Sheri, Venkat Reddy, Kassekert, Luke A., Chen, Shujing, Agniswamy, Johnson, Wang, Yuan-Fang, Hayashi, Hironori, Aoki, Manabu, Weber, Irene T., and Mitsuya, Hiroaki. 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. United States: N. p., 2015. Web. doi:10.1021/acs.jmedchem.5b00900.
Ghosh, Arun K., Martyr, Cuthbert D., Osswald, Heather L., Sheri, Venkat Reddy, Kassekert, Luke A., Chen, Shujing, Agniswamy, Johnson, Wang, Yuan-Fang, Hayashi, Hironori, Aoki, Manabu, Weber, Irene T., & Mitsuya, Hiroaki. 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. United States. https://doi.org/10.1021/acs.jmedchem.5b00900
Ghosh, Arun K., Martyr, Cuthbert D., Osswald, Heather L., Sheri, Venkat Reddy, Kassekert, Luke A., Chen, Shujing, Agniswamy, Johnson, Wang, Yuan-Fang, Hayashi, Hironori, Aoki, Manabu, Weber, Irene T., and Mitsuya, Hiroaki. 2015. "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". United States. https://doi.org/10.1021/acs.jmedchem.5b00900. https://www.osti.gov/servlets/purl/1222022.
@article{osti_1222022,
title = {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},
author = {Ghosh, Arun K. and Martyr, Cuthbert D. and Osswald, Heather L. and Sheri, Venkat Reddy and Kassekert, Luke A. and Chen, Shujing and Agniswamy, Johnson and Wang, Yuan-Fang and Hayashi, Hironori and Aoki, Manabu and Weber, Irene T. and Mitsuya, Hiroaki},
abstractNote = {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.},
doi = {10.1021/acs.jmedchem.5b00900},
url = {https://www.osti.gov/biblio/1222022}, journal = {J. Med. Chem.},
number = 17,
volume = 58,
place = {United States},
year = {Fri Oct 30 00:00:00 EDT 2015},
month = {Fri Oct 30 00:00:00 EDT 2015}
}

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