Design, Synthesis, and Biological and Structural Evaluations of Novel HIV-1 Protease Inhibitors To Combat Drug Resistance
- MIT
A series of new HIV-1 protease inhibitors (PIs) were designed using a general strategy that combines computational structure-based design with substrate-envelope constraints. The PIs incorporate various alcohol-derived P2 carbamates with acyclic and cyclic heteroatomic functionalities into the (R)-hydroxyethylamine isostere. Most of the new PIs show potent binding affinities against wild-type HIV-1 protease and three multidrug resistant (MDR) variants. In particular, inhibitors containing the 2,2-dichloroacetamide, pyrrolidinone, imidazolidinone, and oxazolidinone moieties at P2 are the most potent with Ki values in the picomolar range. Several new PIs exhibit nanomolar antiviral potencies against patient-derived wild-type viruses from HIV-1 clades A, B, and C and two MDR variants. Crystal structure analyses of four potent inhibitors revealed that carbonyl groups of the new P2 moieties promote extensive hydrogen bond interactions with the invariant Asp29 residue of the protease. These structure-activity relationship findings can be utilized to design new PIs with enhanced enzyme inhibitory and antiviral potencies.
- Research Organization:
- Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
- Sponsoring Organization:
- NIGMS
- OSTI ID:
- 1047310
- Journal Information:
- J. Med. Chem., Journal Name: J. Med. Chem. Journal Issue: (14) ; 07, 2012 Vol. 55; ISSN JMCMAR; ISSN 0022-2623
- Country of Publication:
- United States
- Language:
- ENGLISH
Similar Records
Design of HIV-1 protease inhibitors with pyrrolidinones and oxazolidinones as novel P1'-ligands to enhance backbone-binding interactions with protease: synthesis, biological evaluation, and protein-ligand X-ray studies
Design of Highly Potent, Dual-Acting and Central-Nervous-System-Penetrating HIV-1 Protease Inhibitors with Excellent Potency against Multidrug-Resistant HIV-1 Variants
HIV-1 protease inhibitors with a P1 phosphonate modification maintain potency against drug-resistant variants by increased interactions with flap residues
Journal Article
·
Wed Sep 02 00:00:00 EDT 2009
· J. Med. Chem.
·
OSTI ID:1005843
Design of Highly Potent, Dual-Acting and Central-Nervous-System-Penetrating HIV-1 Protease Inhibitors with Excellent Potency against Multidrug-Resistant HIV-1 Variants
Journal Article
·
Mon Feb 12 23:00:00 EST 2018
· ChemMedChem
·
OSTI ID:1435833
HIV-1 protease inhibitors with a P1 phosphonate modification maintain potency against drug-resistant variants by increased interactions with flap residues
Journal Article
·
Thu May 18 00:00:00 EDT 2023
· European Journal of Medicinal Chemistry
·
OSTI ID:2423456