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ACS Chem Biol. 2016 Jan 15;11(1):88-94. doi: 10.1021/acschembio.5b00682. Epub 2015 Nov 3.

N-Methylation as a Strategy for Enhancing the Affinity and Selectivity of RNA-binding Peptides: Application to the HIV-1 Frameshift-Stimulating RNA.

Author information

  • 1OyaGen, Inc. , Rochester, New York 14623, United States.
  • 2Department of Biochemistry, University of Wisconsin , Madison, Wisconsin 53706, United States.
  • 3McArdle Laboratory for Cancer Research and Institute for Molecular Virology, University of Wisconsin-Madison , Madison, Wisconsin 53706, United States.
  • 4Department of Chemistry, SUNY Geneseo , Geneseo, New York 14454, United States.

Abstract

Human Immunodeficiency Virus (HIV) type 1 uses a -1 programmed ribosomal frameshift (-1 PRF) event to translate its enzymes from the same transcript used to encode the virus' structural proteins. The frequency of this event is highly regulated, and significant deviation from the normal 5-10% frequency has been demonstrated to decrease viral infectivity. Frameshifting is primarily regulated by the Frameshift Stimulatory Signal RNA (FSS-RNA), a thermodynamically stable, highly conserved stem loop that has been proposed as a therapeutic target. We describe the design, synthesis, and testing of a series of N-methyl peptides able to bind the HIV-1 FSS RNA stem loop with low nanomolar affinity and high selectivity. Surface plasmon resonance (SPR) data indicates increased affinity is a reflection of a substantially enhanced on rate. Compounds readily penetrate cell membranes and inhibit HIV infectivity in a pseudotyped virus assay. Viral infectivity inhibition correlates with compound-dependent changes in the ratios of Gag and Gag-Pol in virus particles. As the first compounds with both single digit nanomolar affinities for the FSS RNA and an ability to inhibit HIV in cells, these studies support the use of N-methylation for enhancing the affinity, selectivity, and bioactivity of RNA-binding peptides.

PMID:
26496521
PMCID:
PMC4720131
DOI:
10.1021/acschembio.5b00682
[PubMed - indexed for MEDLINE]
Free PMC Article
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