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Strategies for Targeting the Frameshift Stimulatory RNA of HIV-1 with Synthetic Molecules

URL to cite or link to: http://hdl.handle.net/1802/30990

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Thesis (Ph.D.)--University of Rochester. School of Medicine & Dentistry. Dept. of Biochemistry and Biophysics, 2016
Human Immunodeficiency Virus Type 1(HIV-1) has a genome of only nine thousand bases. This small genomic space means the virus can only encode for a few proteins and must use an alternate process to achieve the regulation necessary to propagate the virus. Instead the virus uses structured RNA in the viral messenger RNA to regulate translation. One such regulatory RNA, the frameshift stimulatory signal (FSS), encodes for a -1 programmed ribosomal frameshifting event (PRF). This PRF causes a shift from the open reading frame encoding for gag (structural proteins) to the reading frame encoding for pol (viral enzymes), resulting in the translation of gag-pol, a large poly-protein. This frameshift occurs 5-10% of the time in all HIV-1 isolates, and deviation from this frequency causes a decrease in virion production and virion infectivity. The mechanism of frameshifting is not well understood. The lack of knowledge combined with the potential of altering this process as a novel therapeutic strategy makes the HIV-1 FSS RNA an attractive target against which to develop molecular probes. In this work I describe two chemical modifications that improve a previously described peptide-based molecule that binds the HIV-1 FSS RNA. The first is amide N-methylation. This was found to increase permeability of these compounds by as much as 4 fold, increase the binding affinity for the FSS RNA by 60 fold, and increase the efficacy of these compounds in a pseudotyped infectivity assay by 4 fold. The second modification was substitution of the olefin bioisotere for a triazole. Incorporation of the triazole had a large effect on the acute cellular toxicity of these compounds, reducing the LD50 by >5 Fold, and increasing the therapeutic index by >5 fold.
Contributor(s):
Benjamin L. Miller - Thesis Advisor
ORCID: 0000-0001-9168-8047

Thomas A. Hilimire - Author

Primary Item Type:
Thesis
Language:
English
Subject Keywords:
HIV frameshift RNA small molecule
Sponsor - Description:
National Institute of Allergy and Infectious Diseases (NIAID) - AI049815
National Institute of General Medical Sciences (NIGMS) - GM100788, GM068411
First presented to the public:
5/15/2017
Originally created:
2016
Date will be made available to public:
2017-05-15   
Original Publication Date:
2016
Previously Published By:
University of Rochester School of Medicine and Dentistry
Place Of Publication:
Rochester, N.Y.
Citation:
Extents:
Number of Pages - ix, 136 pages
Illustrations - some color
License Grantor / Date Granted:
Jennifer McCarthy / 2016-06-22 11:43:57.516 ( View License )
Date Deposited
2016-06-22 11:43:57.516
Date Last Updated
2016-06-22 11:49:18.774
Submitter:
Jennifer McCarthy

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