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Title: Design of novel HIV-1 protease inhibitors incorporating isophthalamide-derived P2-P3 ligands: Synthesis, biological evaluation and X-ray structural studies of inhibitor-HIV-1 protease complex

Journal Article · · Bioorganic and Medicinal Chemistry
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  1. Purdue Univ., West Lafayette, IN (United States)
  2. Georgia State Univ., Atlanta, GA (United States)
  3. Kumamoto Univ. of Medicine (Japan)
  4. Kumamoto Univ. of Medicine (Japan); National Cancer Inst., Bethesda, MD (United States); National Center for Global Health and Medicine Research Inst., Tokyo (Japan)
+ Show Author Affiliations

Based upon molecular insights from the X-ray structures of inhibitor-bound HIV-1 protease complexes, we have designed a series of isophthalamide-derived inhibitors incorporating substituted pyrrolidines, piperidines and thiazolidines as P2-P3 ligands for specific interactions in the S2-S3 extended site. Compound 4b has shown an enzyme Ki of 0.025 nM and antiviral IC50 of 69 nM. An X-ray crystal structure of inhibitor 4b-HIV-1 protease complex was determined at 1.33 Å resolution. We have also determined X-ray structure of 3b-bound HIV-1 protease at 1.27 Å resolution. Furthermore, these structures revealed important molecular insight into the inhibitor–HIV-1 protease interactions in the active site.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); National Inst. of Health
Grant/Contract Number:
W-31109-ENG-38
OSTI ID:
1418041
Alternate ID(s):
OSTI ID: 1495866
Journal Information:
Bioorganic and Medicinal Chemistry, Journal Name: Bioorganic and Medicinal Chemistry Journal Issue: 19 Vol. 25; ISSN 0968-0896
Publisher:
ElsevierCopyright Statement
Country of Publication:
United States
Language:
ENGLISH

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Cited By (4)

Diversity-Oriented Synthesis of Diol-Based Peptidomimetics as Potential HIV Protease Inhibitors and Antitumor Agents journal July 2018
Classification of HIV-1 Protease Inhibitors by Machine Learning Methods journal November 2018
Proteases: Pivot Points in Functional Proteomics book October 2018
Highly Selective and Potent Human β‐Secretase 2 (BACE2) Inhibitors against Type 2 Diabetes: Design, Synthesis, X‐ray Structure and Structure–Activity Relationship Studies journal February 2019

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Related Subjects

60 APPLIED LIFE SCIENCES
HIV-1 protease
drug-resistance
X-ray structure
synthesis
isophthalamide