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Title: 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 Article · · ChemMedChem
ORCiD logo [1];  [1];  [1];  [1];  [1];  [2];  [2];  [3];  [4];  [2];  [5]
  1. Purdue Univ., West Lafayette, IN (United States)
  2. Georgia State Univ., Atlanta, GA (United States)
  3. National Cancer Inst., Bethesda, MD (United States); National Center for Global Health and Medicine Research Inst., Tokyo (Japan)
  4. National Center for Global Health and Medicine Research Inst., Tokyo (Japan)
  5. Kumamoto Univ. (Japan); National Cancer Inst., Bethesda, MD (United States); National Center for Global Health and Medicine Research Inst., Tokyo (Japan)
+ Show Author Affiliations

We report the synthesis and biological evaluation of phenylcarboxylic acid and phenylboronic acid containing HIV-1 protease inhibitors and their functional effect on enzyme inhibition and antiviral activity in MT-2 cell lines. Inhibitors bearing bis-THF ligand as P2 ligand and phenylcarboxylic acids and carboxamide as the P2' ligands, showed very potent HIV-1 protease inhibitory activity. However, carboxylic acid containing inhibitors showed very poor antiviral activity relative to carboxamide-derived inhibitors which showed good antiviral IC50 value. Boronic acid derived inhibitor with bis-THF as the P2 ligand showed very potent enzyme inhibitory activity, but it showed lower antiviral activity than darunavir in the same assay. Boronic acid containing inhibitor with a P2-Crn-THF ligand also showed potent enzyme Ki but significantly decreased antiviral activity. We have evaluated antiviral activity against a panel of highly drug-resistant HIV-1 variants. One of the inhibitors maintained good antiviral activity against HIVDRVRP20 and HIVDRVRP30 viruses. We have determined high resolution X-ray structures of two synthetic inhibitors bound to HIV-1 protease and obtained molecular insight into the ligand-binding site interactions.

Research Organization:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES); National Institutes of Health (NIH); Japan Agency for Medical Research and Development (AMED)
Grant/Contract Number:
AI150466; AI150461; R01AI121315; JP15fk0410001; JP18fk0410001; W-31-109-ENG-38
OSTI ID:
1577162
Journal Information:
ChemMedChem, Vol. 14, Issue 21; ISSN 1860-7179
Publisher:
ChemPubSoc EuropeCopyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 10 works
Citation information provided by
Web of Science

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Related Subjects

60 APPLIED LIFE SCIENCES
brain penetration
drug resistance
genetic barriers
HIV-1 protease inhibitors
structure-based design