Discovery of a Branched Peptide That Recognizes the Rev Response Element (RRE) RNA and Blocks HIV-1 Replication
- 5 October 2018
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 61 (21) , 9611-9620
Abstract
We synthesized and screened a unique 46,656-member library composed of unnatural amino acids that revealed several hits against RRE IIB RNA. Among the hit peptides identified, peptide 4A5 was found to be selective against competitor RNAs and inhibited HIV-1 Rev-RRE RNA interaction in cell culture in a p24 ELISA assay. Biophysical characterization in a ribonuclease protection assay suggested that 4A5 bound to the stem-loop region in RRE IIB while SHAPE MaP probing with 234 nt RRE RNA indicated additional interaction with secondary Rev binding sites. Taken together, our investigation suggests that HIV replication is inhibited by multivalent binding of 4A5 with RRE, which blocks subsequent Rev multimerization.Keywords
Funding Information
- National Institute of General Medical Sciences (R01 GM093834)
This publication has 52 references indexed in Scilit:
- Targeting folded RNA: a branched peptideboronic acid that binds to a large surface area of HIV-1 RRE RNAOrganic & Biomolecular Chemistry, 2013
- HIV-1 Antiretroviral Drug TherapyCold Spring Harbor Perspectives in Medicine, 2012
- Toward Targeting RNA Structure: Branched Peptides as Cell-Permeable Ligands to TAR RNAACS Chemical Biology, 2011
- Facile Analysis and Sequencing of Linear and Branched Peptide Boronic Acids by MALDI Mass SpectrometryAnalytical Chemistry, 2011
- Quantitative approaches to monitor protein–nucleic acid interactions using fluorescent probesRNA, 2010
- Screening of a branched peptide library with HIV-1 TAR RNAMolecular BioSystems, 2009
- The Challenge of Finding a Cure for HIV InfectionScience, 2009
- An Approach to the Construction of Tailor-Made Amphiphilic Peptides That Strongly and Selectively Bind to Hairpin RNA TargetsJournal of the American Chemical Society, 2009
- A Solution to Limited Genomic Capacity: Using Adaptable Binding Surfaces to Assemble the Functional HIV Rev Oligomer on RNAMolecular Cell, 2008
- A Heterocyclic Inhibitor of the Rev−RRE Complex Binds to RRE as a DimerBiochemistry, 2001