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Open AccessArticle

Novel pH Selective, Highly Lytic Peptides Based on a Chimeric Influenza Hemagglutinin Peptide/Cell Penetrating Peptide Motif

Merck Research Laboratories, Merck and Co, Inc., West Point, PA 19486, USA
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Academic Editors: Henry Mosberg, Tomi Sawyer and Carrie Haskell-Luevano
Molecules 2019, 24(11), 2079; https://doi.org/10.3390/molecules24112079
Received: 2 May 2019 / Revised: 22 May 2019 / Accepted: 24 May 2019 / Published: 31 May 2019
Delivery of macromolecular cargos such as siRNA to the cytosol after endocytosis remains a critical challenge. Numerous approaches including viruses, lipid nanoparticles, polymeric constructs, and various peptide-based approaches have yet to yield a general solution to this delivery issue. In this manuscript, we describe our efforts to design novel endosomolytic peptides that could be used to facilitate the release of cargos from a late endosomal compartment. These amphiphilic peptides, based on a chimeric influenza hemagglutinin peptide/cell-penetrating peptide (CPP) template, utilize a pH-triggering mechanism in which the peptides are protonated after acidification of the endosome, and thereby adopt an alpha-helical conformation. The helical forms of the peptides are lytically active, while the non-protonated forms are much less or non-lytically active at physiological pH. Starting from an initial lead peptide (INF7-Tat), we systematically modified the sequence of the chimeric peptides to obtain peptides with greatly enhanced lytic activity that maintain good pH selectivity in a red blood cell hemolysis assay. View Full-Text
Keywords: peptides; endosomolytic; amphiphilic; fusogenic; influenza hemagglutinin; RBC lysis peptides; endosomolytic; amphiphilic; fusogenic; influenza hemagglutinin; RBC lysis
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MDPI and ACS Style

Algayer, B.; O’Brien, A.; Momose, A.; Murphy, D.J.; Procopio, W.; Tellers, D.M.; Tucker, T.J. Novel pH Selective, Highly Lytic Peptides Based on a Chimeric Influenza Hemagglutinin Peptide/Cell Penetrating Peptide Motif. Molecules 2019, 24, 2079.

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