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

Debabrata Maity, Sunil Kumar, Francesca Curreli, Asim K. Debnath, Andrew 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 K d 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 (IC 50 =25±1 μm) by rescuing TZM-bl cells infected with the pseudovirus HIV-1HXB-2.

Original languageEnglish (US)
JournalChemistry - A European Journal
DOIs
StatePublished - Jan 1 2019

Fingerprint

RNA
Proteins
Scaffolds (biology)
Scaffolds
Conformations
Assays

Keywords

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

ASJC Scopus subject areas

  • Catalysis
  • Organic Chemistry

Cite this

α-Helix-Mimetic Foldamers for Targeting HIV-1 TAR RNA. / Maity, Debabrata; Kumar, Sunil; Curreli, Francesca; Debnath, Asim K.; Hamilton, Andrew.

In: Chemistry - A European Journal, 01.01.2019.

Research output: Contribution to journalArticle

Maity, Debabrata ; Kumar, Sunil ; Curreli, Francesca ; Debnath, Asim K. ; Hamilton, Andrew. / α-Helix-Mimetic Foldamers for Targeting HIV-1 TAR RNA. In: Chemistry - A European Journal. 2019.
@article{d4d8f894f8864bcf994a648cd245cd3b,
title = "α-Helix-Mimetic Foldamers for Targeting HIV-1 TAR RNA",
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 K d 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 (IC 50 =25±1 μm) by rescuing TZM-bl cells infected with the pseudovirus HIV-1HXB-2.",
keywords = "anti-HIV, foldamers, oligopyridylamides, peptidomimetics, RNA recognition",
author = "Debabrata Maity and Sunil Kumar and Francesca Curreli and Debnath, {Asim K.} and Andrew Hamilton",
year = "2019",
month = "1",
day = "1",
doi = "10.1002/chem.201900139",
language = "English (US)",
journal = "Chemistry - A European Journal",
issn = "0947-6539",
publisher = "Wiley-VCH Verlag",

}

TY - JOUR

T1 - α-Helix-Mimetic Foldamers for Targeting HIV-1 TAR RNA

AU - Maity, Debabrata

AU - Kumar, Sunil

AU - Curreli, Francesca

AU - Debnath, Asim K.

AU - Hamilton, Andrew

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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 K d 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 (IC 50 =25±1 μm) by rescuing TZM-bl cells infected with the pseudovirus HIV-1HXB-2.

AB - 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 K d 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 (IC 50 =25±1 μm) by rescuing TZM-bl cells infected with the pseudovirus HIV-1HXB-2.

KW - anti-HIV

KW - foldamers

KW - oligopyridylamides

KW - peptidomimetics

KW - RNA recognition

UR - http://www.scopus.com/inward/record.url?scp=85064156477&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85064156477&partnerID=8YFLogxK

U2 - 10.1002/chem.201900139

DO - 10.1002/chem.201900139

M3 - Article

JO - Chemistry - A European Journal

JF - Chemistry - A European Journal

SN - 0947-6539

ER -