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Article: Conformational flexibility determines selectivity and antibacterial, antiplasmodial, and anticancer potency of cationic α-helical peptides

TitleConformational flexibility determines selectivity and antibacterial, antiplasmodial, and anticancer potency of cationic α-helical peptides
Authors
KeywordsAggregation
Antimicrobial Peptides
Circular Dichroism (CD)
Malaria
NMR
Peptide Conformation
Plasmodium
Tuberculosis
Proline Kinks
Issue Date2012
PublisherAmerican Society for Biochemistry and Molecular Biology, Inc. The Journal's web site is located at http://www.jbc.org/
Citation
Journal of Biological Chemistry, 2012, v. 287 n. 41, p. 34120-34133 How to Cite?
AbstractWe used a combination of fluorescence, circular dichroism (CD), and NMR spectroscopies in conjunction with size exclusion chromatography to help rationalize the relative antibacterial, antiplasmodial, and cytotoxic activities of a series of proline-free and proline-containing model antimicrobial peptides (AMPs) in terms of their structural properties. When compared with proline-free analogs, proline-containing peptides had greater activity against Gram-negative bacteria, two mammalian cancer cell lines, and intraerythrocytic Plasmodium falciparum, which they were capable of killing without causing hemolysis. In contrast, incorporation of proline did not have a consistent effect on peptide activity against Mycobacterium tuberculosis. In membrane-mimicking environments, structures with high alpha-helix content were adopted by both proline-free and proline-containing peptides. In solution, AMPs generally adopted disordered structures unless their sequences comprised more hydrophobic amino acids or until coordinating phosphate ions were added. Proline-containing peptides resisted ordering induced by either method. The roles of the angle subtended by positively charged amino acids and the positioning of the proline residues were also investigated. Careful positioning of proline residues in AMP sequences is required to enable the peptide to resist ordering and maintain optimal antibacterial activity, whereas varying the angle subtended by positively charged amino acids can attenuate hemolytic potential albeit with a modest reduction in potency. Maintaining conformational flexibility improves AMP potency and selectivity toward bacterial, plasmodial, and cancerous cells while enabling the targeting of intracellular pathogens.
Persistent Identifierhttp://hdl.handle.net/10722/177360
ISSN
2020 Impact Factor: 5.157
2015 SCImago Journal Rankings: 3.151
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorVermeer, LS-
dc.contributor.authorLan, Y-
dc.contributor.authorAbbate, V-
dc.contributor.authorRuh, E-
dc.contributor.authorBui, TT-
dc.contributor.authorWilkinson, LJ-
dc.contributor.authorKanno, T-
dc.contributor.authorJumagulova, E-
dc.contributor.authorKozlowska, J-
dc.contributor.authorPatel, J-
dc.contributor.authorMcIntyre, CA-
dc.contributor.authorYam, WC-
dc.contributor.authorSiu, G-
dc.contributor.authorAtkinson, RA-
dc.contributor.authorLam, JKW-
dc.contributor.authorBansal, SS-
dc.contributor.authorDrake, AF-
dc.contributor.authorMitchell, GH-
dc.contributor.authorMason, AJ-
dc.date.accessioned2012-12-18T05:05:07Z-
dc.date.available2012-12-18T05:05:07Z-
dc.date.issued2012-
dc.identifier.citationJournal of Biological Chemistry, 2012, v. 287 n. 41, p. 34120-34133-
dc.identifier.issn0021-9258-
dc.identifier.urihttp://hdl.handle.net/10722/177360-
dc.description.abstractWe used a combination of fluorescence, circular dichroism (CD), and NMR spectroscopies in conjunction with size exclusion chromatography to help rationalize the relative antibacterial, antiplasmodial, and cytotoxic activities of a series of proline-free and proline-containing model antimicrobial peptides (AMPs) in terms of their structural properties. When compared with proline-free analogs, proline-containing peptides had greater activity against Gram-negative bacteria, two mammalian cancer cell lines, and intraerythrocytic Plasmodium falciparum, which they were capable of killing without causing hemolysis. In contrast, incorporation of proline did not have a consistent effect on peptide activity against Mycobacterium tuberculosis. In membrane-mimicking environments, structures with high alpha-helix content were adopted by both proline-free and proline-containing peptides. In solution, AMPs generally adopted disordered structures unless their sequences comprised more hydrophobic amino acids or until coordinating phosphate ions were added. Proline-containing peptides resisted ordering induced by either method. The roles of the angle subtended by positively charged amino acids and the positioning of the proline residues were also investigated. Careful positioning of proline residues in AMP sequences is required to enable the peptide to resist ordering and maintain optimal antibacterial activity, whereas varying the angle subtended by positively charged amino acids can attenuate hemolytic potential albeit with a modest reduction in potency. Maintaining conformational flexibility improves AMP potency and selectivity toward bacterial, plasmodial, and cancerous cells while enabling the targeting of intracellular pathogens.-
dc.languageeng-
dc.publisherAmerican Society for Biochemistry and Molecular Biology, Inc. The Journal's web site is located at http://www.jbc.org/-
dc.relation.ispartofJournal of Biological Chemistry-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectAggregation-
dc.subjectAntimicrobial Peptides-
dc.subjectCircular Dichroism (CD)-
dc.subjectMalaria-
dc.subjectNMR-
dc.subjectPeptide Conformation-
dc.subjectPlasmodium-
dc.subjectTuberculosis-
dc.subjectProline Kinks-
dc.titleConformational flexibility determines selectivity and antibacterial, antiplasmodial, and anticancer potency of cationic α-helical peptides-
dc.typeArticle-
dc.identifier.emailYam, WC: wcyam@hkucc.hku.hk-
dc.identifier.emailSiu, G: gilman06@hkucc.hku.hk-
dc.identifier.emailLam, JKW: jkwlam@hku.hk-
dc.identifier.authorityYam, WC=rp00313-
dc.identifier.authorityLam, JKW=rp01346-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1074/jbc.M112.359067-
dc.identifier.pmid22869378-
dc.identifier.pmcidPMC3464521-
dc.identifier.scopuseid_2-s2.0-84867259108-
dc.identifier.hkuros212592-
dc.identifier.hkuros225799-
dc.identifier.volume287-
dc.identifier.issue41-
dc.identifier.spage34120-
dc.identifier.epage34133-
dc.identifier.isiWOS:000309654200018-
dc.publisher.placeUnited States-
dc.identifier.citeulike11430576-
dc.identifier.issnl0021-9258-

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