Superior HIV-1 TAR binders with conformationally constrained R52 arginine mimics in the Tat(48-57) peptide

TitleSuperior HIV-1 TAR binders with conformationally constrained R52 arginine mimics in the Tat(48-57) peptide
Publication TypeJournal Article
Year of Publication2018
AuthorsBhosle, GS, Kharche, S, Kumar, S, Sengupta, D, Maiti, S, Fernandes, M
JournalChemmedchem
Volume13
Issue3
Pagination220-226
Date PublishedFEB
Type of ArticleArticle
ISSN1860-7179
Keywordsantiviral agents, arginine mimics, RNA, Tat peptide analogues, Tat-TAR binding
Abstract

We report a 100-fold increase in binding affinity of the Tat(48-57) peptide to HIV-1 transcriptional activator-responsive element (TAR) RNA by replacing Arg52, an essential and critical residue for Tat's specific binding, with (2S,4S)-4-guanidinoproline. The resulting Tat1M peptide is a far superior binder than Tat1M, a peptide containing another conformationally constrained arginine mimic, (2S,4S)-4-amino-N-(3-guanidinopropyl)proline, or even the control Tat peptide (CtrlTat) itself. Our observations are supported by circular dichroism (CD), isothermal titration calorimetry (ITC), gel electrophoresis and UV spectroscopy studies. Molecular dynamics simulations suggest increased interactions between the more compact Tat1M and TAR RNA, relative to CtrlTat. The CD signature of the RNA itself remains largely unchanged upon binding of the peptides. The Tat mimetics further have better cell uptake properties than the control Tat peptide, thus increasing their potential application as specific TAR-binding molecules.

DOI10.1002/cmdc.201700653
Type of Journal (Indian or Foreign)

Foreign

Impact Factor (IF)

3.225

Divison category: 
Organic Chemistry
Physical and Materials Chemistry