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Characterization of cholesterol targeting antimicrobial peptides and assessment of their antiviral activity in vitro

Hasek, Mary (2014) Characterization of cholesterol targeting antimicrobial peptides and assessment of their antiviral activity in vitro. Master's Thesis, University of Pittsburgh. (Unpublished)

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Abstract

In recent decades, efforts have been made to rationally design antimicrobial peptides (AMPs) for use as alternative therapeutics. The de novo designed AMP WLBU2 is a 24 residue long cationic, α-helical peptide. Antimicrobial activity of WLBU2 is predicted to be based on peptide interaction with lipid membranes leading to bilayer disruption. Antibacterial activity of WLBU2 has been displayed against a wide-range of antibiotic resistant Gram positive and Gram negative bacteria based on charge interactions between the cationic peptide and the anionic bacterial membrane lipids. Preliminary experiments indicated WLBU2 has antiviral activity against various enveloped viruses suggesting the potential for development of a broad spectrum antiviral treatment. While viral envelopes do not have the same negative surface charge presumed to be the basis for antibacterial activity of WLBU2, most mammalian virus membranes are enriched for cholesterol relative to host cells. We hypothesized that specifically targeting WLBU2 to cholesterol rich membranes would increase antiviral activity against a broad range of enveloped mammalian viruses. Addition of the cholesterol recognition amino acid consensus (CRAC) motif is predicted to direct WLBU2 to cholesterol rich viral envelopes, thereby disrupting the membrane and leading to virus inactivation. When tested against human immunodeficiency virus (HIV), influenza A, and dengue virus (DENV), computationally designed CRAC motif containing peptides and unmodified WLBU2 activity varied across the panel of viruses tested. Antiviral activity was observed against influenza A and DENV, and CRAC motif containing peptides were about 10-fold more effective against DENV than unmodified WLBU2. Therapeutic indices of CRAC motif containing peptides were similar to that observed for unmodified WLBU2. These findings suggest that AMPs can be designed to enhance antiviral activity, representing a novel therapeutic design with the potential for significant public health impact against global diseases such as influenza and DENV.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Hasek, Marymaryhasek@gmail.com
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairMontelaro, Ronaldrmont@pitt.eduRMONT
Committee MemberGupta, Phalgunipgupta1@pitt.eduPGUPTA1
Committee MemberReinhart, Todd A.reinhar@pitt.eduREINHAR
Date: 29 September 2014
Date Type: Publication
Defense Date: 25 June 2014
Approval Date: 29 September 2014
Submission Date: 8 July 2014
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Number of Pages: 74
Institution: University of Pittsburgh
Schools and Programs: Graduate School of Public Health > Infectious Diseases and Microbiology
Degree: MS - Master of Science
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords: antimicrobial, peptides, cholesterol, membrane, antiviral
Date Deposited: 29 Sep 2014 20:43
Last Modified: 01 Sep 2019 05:15
URI: http://d-scholarship.pitt.edu/id/eprint/22237

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