The cationic tetradecapeptide mastoparan as a privileged structure for drug discovery: Enhanced antimicrobial properties of mitoparan analogues modified at position-14

2.50
Hdl Handle:
http://hdl.handle.net/2436/621066
Title:
The cationic tetradecapeptide mastoparan as a privileged structure for drug discovery: Enhanced antimicrobial properties of mitoparan analogues modified at position-14
Authors:
Howl, John; Howl, Lewis; Jones, Sarah
Abstract:
Mastoparan (MP) peptides, distributed in insect venoms, induce a local inflammatory response post envenomation. Most endogenous MPs share common structural elements within a tetradecapeptide sequence that adopts an amphipathic helix whilst traversing biological membranes and when bound to an intracellular protein target. Rational modifications to increase cationic charge density and amphipathic helicity engineered mitoparan (MitP), a mitochondriotoxic bioportide and potent secretagogue. Following intracellular translocation, MitP is accreted by mitochondria thus indicating additional utility as an antimicrobial agent. Hence, the objectives of this study were to compare the antimicrobial activities of a structurally diverse set of cationic cell penetrating peptides, including both MP and MitP sequences, and to chemically engineer analogues of MitP for potential therapeutic applications. Herein, we confirm that, like MP, MitP is a privileged structure for the development of antimicrobial peptides active against both prokaryotic and eukaryotic pathogens. Collectively, MitP and target-selective chimeric analogues are broad spectrum antibiotics, with the Gram-negative A. baumannii demonstrating particular susceptibility. Modifications of MitP by amino acid substitution at position-14 produced peptides, Δ14MitP analogues, with unique pharmacodynamic properties. One example, [Ser14]MitP, lacks both cytotoxicity against human cell lines and mast cell secretory activity yet retains selective activity against the encapsulated yeast C. neoformans.
Citation:
The cationic tetradecapeptide mastoparan as a privileged structure for drug discovery: Enhanced antimicrobial properties of mitoparan analogues modified at position-14 2018, 101:95 Peptides
Publisher:
Elsevier
Journal:
Peptides (Volume 101, March 2018, Pages 95-105)
Issue Date:
Mar-2018
URI:
http://hdl.handle.net/2436/621066
DOI:
10.1016/j.peptides.2018.01.007
Additional Links:
http://linkinghub.elsevier.com/retrieve/pii/S0196978118300135
Type:
Article
Language:
en
ISSN:
0196-9781
Appears in Collections:
FSE

Full metadata record

DC FieldValue Language
dc.contributor.authorHowl, Johnen
dc.contributor.authorHowl, Lewisen
dc.contributor.authorJones, Sarahen
dc.date.accessioned2018-02-01T12:39:50Z-
dc.date.available2018-02-01T12:39:50Z-
dc.date.issued2018-03-
dc.identifier.citationThe cationic tetradecapeptide mastoparan as a privileged structure for drug discovery: Enhanced antimicrobial properties of mitoparan analogues modified at position-14 2018, 101:95 Peptidesen
dc.identifier.issn0196-9781en
dc.identifier.doi10.1016/j.peptides.2018.01.007-
dc.identifier.urihttp://hdl.handle.net/2436/621066-
dc.description.abstractMastoparan (MP) peptides, distributed in insect venoms, induce a local inflammatory response post envenomation. Most endogenous MPs share common structural elements within a tetradecapeptide sequence that adopts an amphipathic helix whilst traversing biological membranes and when bound to an intracellular protein target. Rational modifications to increase cationic charge density and amphipathic helicity engineered mitoparan (MitP), a mitochondriotoxic bioportide and potent secretagogue. Following intracellular translocation, MitP is accreted by mitochondria thus indicating additional utility as an antimicrobial agent. Hence, the objectives of this study were to compare the antimicrobial activities of a structurally diverse set of cationic cell penetrating peptides, including both MP and MitP sequences, and to chemically engineer analogues of MitP for potential therapeutic applications. Herein, we confirm that, like MP, MitP is a privileged structure for the development of antimicrobial peptides active against both prokaryotic and eukaryotic pathogens. Collectively, MitP and target-selective chimeric analogues are broad spectrum antibiotics, with the Gram-negative A. baumannii demonstrating particular susceptibility. Modifications of MitP by amino acid substitution at position-14 produced peptides, Δ14MitP analogues, with unique pharmacodynamic properties. One example, [Ser14]MitP, lacks both cytotoxicity against human cell lines and mast cell secretory activity yet retains selective activity against the encapsulated yeast C. neoformans.en
dc.language.isoenen
dc.publisherElsevieren
dc.relation.urlhttp://linkinghub.elsevier.com/retrieve/pii/S0196978118300135en
dc.rightsArchived with thanks to Peptidesen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.subjectMastoparanen
dc.subjectMitoparanen
dc.subjectAntimicrobialen
dc.subjectAntifungalen
dc.subjectCell penetrating peptideen
dc.titleThe cationic tetradecapeptide mastoparan as a privileged structure for drug discovery: Enhanced antimicrobial properties of mitoparan analogues modified at position-14en
dc.typeArticleen
dc.identifier.journalPeptides (Volume 101, March 2018, Pages 95-105)en
dc.date.accepted2018-01-
rioxxterms.funderInternalen
rioxxterms.identifier.projectUoW010218SJen
rioxxterms.versionAMen
rioxxterms.licenseref.urihttps://creativecommons.org/CC BY-NC-ND 4.0en
rioxxterms.licenseref.startdate2019-03-01en
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