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Design, Synthesis, Biological Evaluation, and X-ray Studies of HIV-1 Protease Inhibitors with Modified P2' Ligands of Darunavir

Journal Article · · ChemMedChem
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  1. Purdue Univ., West Lafayette, IN (United States)
  2. Georgia State Univ., Atlanta, GA (United States)
  3. Kumamoto Univ. School of Medicine (Japan)
  4. Kumamoto Univ. School of Medicine (Japan); National Cancer Inst., Bethesda, MD (United States); National Center for Global Heath and Medicine, Tokyo (Japan)
+ Show Author Affiliations
The structure–based design, synthesis, and biological evaluation of a series of nonpeptidic HIV–1 protease inhibitors with rationally designed P2' ligands are described. The inhibitors are designed to enhance backbone binding interactions, particularly at the S2' subsite. Synthesis of inhibitors was carried out efficiently. The stereochemistry of alcohol functionalities of the P2' ligands was set by asymmetric reduction of the corresponding ketone using (R,R)– or (S,S)–Noyori catalysts. A number of inhibitors displayed very potent enzyme inhibitory and antiviral activity. Inhibitors 3g and 3h showed enzyme Ki values of 27.9 and 49.7 pm and antiviral activity of 6.2 and 3.9 nm, respectively. These inhibitors also remained quite potent against darunavir–resistant HIV–1 variants. In conclusion, an X–ray structure of inhibitor 3g in complex with HIV–1 protease revealed key interactions in the S2' subsite.
Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
National Inst. of Health
OSTI ID:
1422231
Journal Information:
ChemMedChem, Journal Name: ChemMedChem Journal Issue: 23 Vol. 12; ISSN 1860-7179
Publisher:
ChemPubSoc EuropeCopyright Statement
Country of Publication:
United States
Language:
ENGLISH

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Potent HIV‐1 Protease Inhibitors Containing Carboxylic and Boronic Acids: Effect on Enzyme Inhibition and Antiviral Activity and Protein‐Ligand X‐ray Structural Studies journal October 2019

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
HIV-1 protease inhibitors
P2′ ligands
drug resistance
pharmacokinetics
structure-based design