Open AccessDesign 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(s) -
Arun K. Ghosh,
Cuthbert D. Martyr,
Heather L. Osswald,
Venkat Reddy Sheri,
Luke A. Kassekert,
Shujing Chen,
Johnson Agniswamy,
Yuan Fang Wang,
Hironori Hayashi,
Manabu Aoki,
Irene T. Weber,
Hiroaki Mitsuya
Publication year - 2015
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.5b00900
Subject(s) - chemistry , darunavir , tetrahydrofuran , stereochemistry , protease , hiv 1 protease , ligand (biochemistry) , hydrogen bond , active site , chemical synthesis , enzyme inhibitor , enzyme , combinatorial chemistry , human immunodeficiency virus (hiv) , in vitro , biochemistry , molecule , organic chemistry , receptor , virology , antiretroviral therapy , solvent , viral load , biology
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.