Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 52, Issue 13, Pages 3902-3914Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm900303m
Keywords
-
Categories
Funding
- Intramural NIH HHS Funding Source: Medline
- NIGMS NIH HHS [R01 GM062920-10, R01 GM062920, R01 GM062920-11A1, R01 GM053386, GM53386, R37 GM053386, R01 GM053386-14, U01 GM062920, GM62920] Funding Source: Medline
Ask authors/readers for more resources
Structure-based design,. synthesis, and biological evaluation of a series of novel HIV-1 protease inhibitors are described. In an effort to enhance interactions with protease backbone atoms, we have incorporated stereochemically defined methyl-2-pyrrolidonone and methyl oxazolidinone as the P1'-ligands. These ligands are designed to interact with Gly-27' carbonyl and Arg-8 side chain in the S1'-subsite of the HIV protease. We have investigated the potential of these ligands in combination with our previously developed bis-tetrahydrofuran (bis-THF) and cyclopentanyltetrahydrofuran (Cp-THF) as the P2-ligands. Inhibitor 19b with a (R)-aminomethyl-2-pyrrolidinone and a Cp-THF was shown to be the most potent compound. This inhibitor maintained near full potency against multi-PI-resistant clinical HIV-1 variants. A high resolution protein-ligand X-ray crystal structure of 19b-bound HIV-1 protease revealed that the P1'-pyrrolidinone heterocycle and the P2-Cp-ligand are involved in several critical interactions with the backbone atoms in the S1' and S2 subsites of HIV-1 protease.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available