α-Helix-Mimetic Foldamers for Targeting HIV-1 TAR RNA

Debabrata Maity, Sunil Kumar, Francesca Curreli, Asim K. Debnath, Andrew D. Hamilton

Research output: Contribution to journalArticle

Abstract

An oligopyridylamide-based foldamer approach has been employed to target HIV TAR RNA-TAT assembly as a model system to study RNA-protein interactions. The oligopyridylamide scaffold adopts a constrained conformation which presents surface functionalities at distinct spatial locations and mimic the chemical features of the secondary structure of proteins. We have designed a library of oligopyridylamides containing diverse surface functionalities which mimic the side chain residues of the TAT protein domain. The interaction of TAR RNA and TAT plays a pivotal role in facilitating HIV replication. The library was screened using various fluorescent based assays to identify antagonists of the TAR RNA-TAT complex. A tricationic oligopyridylamide ADH-19, possessed the highest affinity towards TAR and efficiently inhibited the TAR RNA-TAT interaction with apparent Kd of 4.1±1.0 μm. Spectroscopic studies demonstrated that ADH-19 interacts with the bulge and the lower bulge regions of TAR RNA, the domains important for TAT interaction. ADH-19 demonstrated appreciable in vivo efficacy (IC50=25±1 μm) by rescuing TZM-bl cells infected with the pseudovirus HIV-1HXB-2.

Original languageEnglish (US)
Pages (from-to)7265-7269
Number of pages5
JournalChemistry - A European Journal
Volume25
Issue number30
DOIs
StatePublished - May 28 2019

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Keywords

  • RNA recognition
  • anti-HIV
  • foldamers
  • oligopyridylamides
  • peptidomimetics

ASJC Scopus subject areas

  • Catalysis
  • Organic Chemistry

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