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

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 m...

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Main Authors:	Bethany Algayer, Ann O’Brien, Aaron Momose, Dennis J. Murphy, William Procopio, David M. Tellers, Thomas J. Tucker
Format:	Article
Language:	English
Published:	MDPI AG 2019-05-01
Series:	Molecules
Subjects:	peptides endosomolytic amphiphilic fusogenic influenza hemagglutinin RBC lysis
Online Access:	https://www.mdpi.com/1420-3049/24/11/2079

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spelling	doaj-5240c8215b514217a9d43fa17ba1d6bd2020-11-25T01:30:25ZengMDPI AGMolecules1420-30492019-05-012411207910.3390/molecules24112079molecules24112079Novel pH Selective, Highly Lytic Peptides Based on a Chimeric Influenza Hemagglutinin Peptide/Cell Penetrating Peptide MotifBethany Algayer0Ann O’Brien1Aaron Momose2Dennis J. Murphy3William Procopio4David M. Tellers5Thomas J. Tucker6Merck Research Laboratories, Merck and Co, Inc., West Point, PA 19486, USAMerck Research Laboratories, Merck and Co, Inc., West Point, PA 19486, USAMerck Research Laboratories, Merck and Co, Inc., West Point, PA 19486, USAMerck Research Laboratories, Merck and Co, Inc., West Point, PA 19486, USAMerck Research Laboratories, Merck and Co, Inc., West Point, PA 19486, USAMerck Research Laboratories, Merck and Co, Inc., West Point, PA 19486, USAMerck Research Laboratories, Merck and Co, Inc., West Point, PA 19486, USADelivery 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.https://www.mdpi.com/1420-3049/24/11/2079peptidesendosomolyticamphiphilicfusogenicinfluenza hemagglutininRBC lysis
collection	DOAJ
language	English
format	Article
sources	DOAJ
author	Bethany Algayer Ann O’Brien Aaron Momose Dennis J. Murphy William Procopio David M. Tellers Thomas J. Tucker
spellingShingle	Bethany Algayer Ann O’Brien Aaron Momose Dennis J. Murphy William Procopio David M. Tellers Thomas J. Tucker Novel pH Selective, Highly Lytic Peptides Based on a Chimeric Influenza Hemagglutinin Peptide/Cell Penetrating Peptide Motif Molecules peptides endosomolytic amphiphilic fusogenic influenza hemagglutinin RBC lysis
author_facet	Bethany Algayer Ann O’Brien Aaron Momose Dennis J. Murphy William Procopio David M. Tellers Thomas J. Tucker
author_sort	Bethany Algayer
title	Novel pH Selective, Highly Lytic Peptides Based on a Chimeric Influenza Hemagglutinin Peptide/Cell Penetrating Peptide Motif
title_short	Novel pH Selective, Highly Lytic Peptides Based on a Chimeric Influenza Hemagglutinin Peptide/Cell Penetrating Peptide Motif
title_full	Novel pH Selective, Highly Lytic Peptides Based on a Chimeric Influenza Hemagglutinin Peptide/Cell Penetrating Peptide Motif
title_fullStr	Novel pH Selective, Highly Lytic Peptides Based on a Chimeric Influenza Hemagglutinin Peptide/Cell Penetrating Peptide Motif
title_full_unstemmed	Novel pH Selective, Highly Lytic Peptides Based on a Chimeric Influenza Hemagglutinin Peptide/Cell Penetrating Peptide Motif
title_sort	novel ph selective, highly lytic peptides based on a chimeric influenza hemagglutinin peptide/cell penetrating peptide motif
publisher	MDPI AG
series	Molecules
issn	1420-3049
publishDate	2019-05-01
description	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.
topic	peptides endosomolytic amphiphilic fusogenic influenza hemagglutinin RBC lysis
url	https://www.mdpi.com/1420-3049/24/11/2079
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Novel pH Selective, Highly Lytic Peptides Based on a Chimeric Influenza Hemagglutinin Peptide/Cell Penetrating Peptide Motif

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