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

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 afinity 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.

Authors:
;  [1];  [1];  [2];  [2];  [3];  [3];  [4];  [2];  [1];
+ Show Author Affiliations
  1. OyaGen, Inc., Rochester, New York 14623, United States
  2. Department of Biochemistry, University of Wisconsin, Madison, Wisconsin 53706, United States
  3. McArdle Laboratory for Cancer Research and Institute for Molecular Virology, University of Wisconsin-Madison, Madison, Wisconsin 53706, United States
  4. Department of Chemistry, SUNY Geneseo, Geneseo, New York 14454, United States
Publication Date:
Research Org.:
State Univ. of New York (SUNY), Plattsburgh, NY (United States). Research Foundation
Sponsoring Org.:
USDOE; National Institutes of Health (NIH)
OSTI Identifier:
1224931
Alternate Identifier(s):
OSTI ID: 1436285
Grant/Contract Number:  
SC0005129; GM100788; GM072447
Resource Type:
Published Article
Journal Name:
ACS Chemical Biology
Additional Journal Information:
Journal Name: ACS Chemical Biology Journal Volume: 11 Journal Issue: 1; Journal ID: ISSN 1554-8929
Publisher:
American Chemical Society
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Hilimire, Thomas A., Bennett, Ryan P., Stewart, Ryan A., Garcia-Miranda, Pablo, Blume, Alex, Becker, Jordan, Sherer, Nathan, Helms, Eric D., Butcher, Samuel E., Smith, Harold C., and Miller, Benjamin L. N -Methylation as a Strategy for Enhancing the Affinity and Selectivity of RNA-binding Peptides: Application to the HIV-1 Frameshift-Stimulating RNA. United States: N. p., 2015. Web. doi:10.1021/acschembio.5b00682.
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Hilimire, Thomas A., Bennett, Ryan P., Stewart, Ryan A., Garcia-Miranda, Pablo, Blume, Alex, Becker, Jordan, Sherer, Nathan, Helms, Eric D., Butcher, Samuel E., Smith, Harold C., & Miller, Benjamin L. N -Methylation as a Strategy for Enhancing the Affinity and Selectivity of RNA-binding Peptides: Application to the HIV-1 Frameshift-Stimulating RNA. United States. https://doi.org/10.1021/acschembio.5b00682
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Hilimire, Thomas A., Bennett, Ryan P., Stewart, Ryan A., Garcia-Miranda, Pablo, Blume, Alex, Becker, Jordan, Sherer, Nathan, Helms, Eric D., Butcher, Samuel E., Smith, Harold C., and Miller, Benjamin L. Tue . "N -Methylation as a Strategy for Enhancing the Affinity and Selectivity of RNA-binding Peptides: Application to the HIV-1 Frameshift-Stimulating RNA". United States. https://doi.org/10.1021/acschembio.5b00682.
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@article{osti_1224931,
title = {N -Methylation as a Strategy for Enhancing the Affinity and Selectivity of RNA-binding Peptides: Application to the HIV-1 Frameshift-Stimulating RNA},
author = {Hilimire, Thomas A. and Bennett, Ryan P. and Stewart, Ryan A. and Garcia-Miranda, Pablo and Blume, Alex and Becker, Jordan and Sherer, Nathan and Helms, Eric D. and Butcher, Samuel E. and Smith, Harold C. and Miller, Benjamin L.},
abstractNote = {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 afinity 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.},
doi = {10.1021/acschembio.5b00682},
journal = {ACS Chemical Biology},
number = 1,
volume = 11,
place = {United States},
year = {Tue Nov 03 00:00:00 EST 2015},
month = {Tue Nov 03 00:00:00 EST 2015}
}
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https://doi.org/10.1021/acschembio.5b00682
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