Synthesis and structure-activity relationship studies of hiv-1 virion infectivity factor (vif) inhibitors that block viral replication

Akbar Ali, Jinhua Wang, Robin S. Nathans, Hong Cao, Natalia Sharova, Mario Stevenson, Tariq M. Rana

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

The human immunodeficiency virus1 (HIV-1) virion infectivity factor (Vif) protein, essential for in vivo viral replication, protects the virus from innate antiviral cellular factor apolipoproteinB mRNA-editing, enzyme-catalytic, polypeptide-like3G (APOBEC3G; A3G) and is an attractive target for the development of novel antiviral therapeutics. We have evaluated the structure-activity relationships of N-(2-methoxyphenyl)-2-((4-nitrophenyl)thio)benzamide (RN-18), a small molecule recently identified as an inhibitor of Vif function that blocks viral replication only in nonpermissive cells expressing A3G, by inhibiting Vif-A3G interactions. Microwave-assisted cross-coupling reactions were developed to prepare a series of RN18 analogues with diverse linkages and substitutions on the phenyl rings. A dual cell-based assay system was used to assess antiviral activity against wild-type HIV-1 in both nonpermissive (H9) and permissive (MT4) cells that also allowed evaluation of specificity. In general, variations of phenyl substitutions were detrimental to antiviral potency and specificity, but isosteric replacements of amide and ether linkages were relatively well tolerated. These structure-activity relationship data define structural requirements for Vif-specific activity, identify new compounds with improved antiviral potency and specificity, and provide leads for further exploration to develop new antiviral therapeutics.

Original languageEnglish
Pages (from-to)1217-1229
Number of pages13
JournalChemMedChem
Volume7
Issue number7
DOIs
StatePublished - Jul 1 2012

Fingerprint

Structure-Activity Relationship
Virion
Antiviral Agents
Substitution reactions
Cross Reactions
Virus Replication
Microwaves
Viruses
Amides
Ether
Assays
Cells
Messenger RNA
Peptides
Molecules
Enzymes
Therapeutics
Proteins

Keywords

  • Antiviral agents
  • Drug discovery
  • HIV-1 Vif
  • Inhibitors
  • Protein-protein interactions
  • Structure-activity relationships

ASJC Scopus subject areas

  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry
  • Molecular Medicine

Cite this

Synthesis and structure-activity relationship studies of hiv-1 virion infectivity factor (vif) inhibitors that block viral replication. / Ali, Akbar; Wang, Jinhua; Nathans, Robin S.; Cao, Hong; Sharova, Natalia; Stevenson, Mario; Rana, Tariq M.

In: ChemMedChem, Vol. 7, No. 7, 01.07.2012, p. 1217-1229.

Research output: Contribution to journalArticle

Ali, Akbar ; Wang, Jinhua ; Nathans, Robin S. ; Cao, Hong ; Sharova, Natalia ; Stevenson, Mario ; Rana, Tariq M. / Synthesis and structure-activity relationship studies of hiv-1 virion infectivity factor (vif) inhibitors that block viral replication. In: ChemMedChem. 2012 ; Vol. 7, No. 7. pp. 1217-1229.
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