Pushing the envelope: enhancing the potency of D-peptide HIV entry inhibitors by membrane localization

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Publication Type dissertation
School or College School of Medicine
Department Biochemistry
Author Francis, James Nicholas
Title Pushing the envelope: enhancing the potency of D-peptide HIV entry inhibitors by membrane localization
Date 2012-12
Description Thirty four million people are infected with HIV, the causative agent of acquired immunodeficiency syndrome (AIDS), which has caused an estimated 25 million deaths in the three decades since the virus was identified. Dramatic progress has been made in understanding the viral lifecycle, enabling the development of safe and effective antiretroviral therapies that greatly reduce AIDS-associated mortality. Viral entry is mediated by the viral glycoprotein, Env. Env, composed of gp120 and gp41 subunits, adopts a transient conformation known as the prehairpin intermediate during fusion that is vulnerable to inhibition by peptides that bind the gp41 N-trimer region. Our lab has developed D-peptide inhibitors that bind to the N-trimer and prevent viral entry. The HIV lifecycle, current therapeutics, and emerging fields of HIV prevention and treatment are described in Chapter 1. Chapter 2 describes the discovery of highly potent D-peptide inhibitors of entry that bind to the N-trimer region and inhibit viral entry. These peptides, optimized by structure-guided mirror-image phage display, inhibit viral entry with nM potency. Trimerization of D-peptide inhibitors yields significant further improvement in potency due to avidity, and inhibit a broad panel of primary isolates. D-peptides are insensitive to proteolysis, a significant advantage over L-peptide inhibitors of entry.
Type Text
Publisher University of Utah
Subject Cholesterol; D-peptide; Gp41; HIV; HIV entry
Dissertation Institution University of Utah
Dissertation Name Doctor of Philosophy
Language eng
Rights Management Copyright © James Nicholas Francis 2012
Format Medium application/pdf
Format Extent 2,571,054 bytes
Identifier etd3/id/3442
ARK ark:/87278/s6dr63qr
Setname ir_etd
ID 196998
Reference URL https://collections.lib.utah.edu/ark:/87278/s6dr63qr