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Synthesis, Antiviral Potency, in Vitro ADMET, and X-ray Structure of Potent CD4 Mimics as Entry Inhibitors That Target the Phe43 Cavity of HIV-1 gp120.

Abstract
In our attempt to optimize the lead HIV-1 entry antagonist, NBD-11021, we present in this study the rational design and synthesis of 60 new analogues and determination of their antiviral activity in a single-cycle and a multicycle infection assay to derive a comprehensive structure-activity relationship (SAR). Two of these compounds, NBD-14088 and NBD-14107, showed significant improvement in antiviral activity compared to the lead entry antagonist in a single-cycle assay against a large panel of Env-pseudotyped viruses. The X-ray structure of a similar compound, NBD-14010, confirmed the binding mode of the newly designed compounds. The in vitro ADMET profiles of these compounds are comparable to that of the most potent attachment inhibitor BMS-626529, a prodrug of which is currently undergoing phase III clinical trials. The systematic study presented here is expected to pave the way for improving the potency, toxicity, and ADMET profile of this series of compounds with the potential to be moved to the early preclinical development.
AuthorsFrancesca Curreli, Young Do Kwon, Dmitry S Belov, Ranjith R Ramesh, Alexander V Kurkin, Andrea Altieri, Peter D Kwong, Asim K Debnath
JournalJournal of medicinal chemistry (J Med Chem) Vol. 60 Issue 7 Pg. 3124-3153 (04 13 2017) ISSN: 1520-4804 [Electronic] United States
PMID28266845 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Anti-HIV Agents
  • CD4 Antigens
  • HIV Envelope Protein gp120
  • NBD-11021
  • Pyrroles
  • Thiazoles
Topics
  • Anti-HIV Agents (chemistry, pharmacology)
  • Biomimetic Materials (chemistry, pharmacology)
  • CD4 Antigens (chemistry, pharmacology)
  • Cell Line
  • Crystallography, X-Ray
  • HIV Envelope Protein gp120 (chemistry, metabolism)
  • HIV Infections (drug therapy, metabolism, virology)
  • HIV-1 (drug effects, metabolism, physiology)
  • Humans
  • Molecular Docking Simulation
  • Molecular Targeted Therapy
  • Pyrroles (chemistry, pharmacology)
  • Structure-Activity Relationship
  • Thiazoles (chemistry, pharmacology)
  • Virus Internalization (drug effects)

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