Investigation of cationicity and structure of pseudin-2 analogues for enhanced bacterial selectivity and anti-inflammatory activity

Abstract Pseudin-2 (Ps), isolated from the frog Pseudis paradoxa, exhibits potent antibacterial activity and cytotoxicity. To develop antimicrobial peptides with anti-inflammatory activity and low cytotoxicity, we designed Ps analogues with Lys substitutions, resulting in elevated amphipathic α-heli...

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Autores principales:	Dasom Jeon, Min-Cheol Jeong, Binu Jacob, Jeong Kyu Bang, Eun-Hee Kim, Chaejoon Cheong, In Duk Jung, Yoonkyung Park, Yangmee Kim
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/97a022e25a9a4df2932b8be12cb23e86
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spelling	oai:doaj.org-article:97a022e25a9a4df2932b8be12cb23e862021-12-02T15:06:10ZInvestigation of cationicity and structure of pseudin-2 analogues for enhanced bacterial selectivity and anti-inflammatory activity10.1038/s41598-017-01474-02045-2322https://doaj.org/article/97a022e25a9a4df2932b8be12cb23e862017-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-01474-0https://doaj.org/toc/2045-2322Abstract Pseudin-2 (Ps), isolated from the frog Pseudis paradoxa, exhibits potent antibacterial activity and cytotoxicity. To develop antimicrobial peptides with anti-inflammatory activity and low cytotoxicity, we designed Ps analogues with Lys substitutions, resulting in elevated amphipathic α-helical structure and cationicity. We further substituted Gly11 with Pro (Ps-P analogues) to increase bacterial cell selectivity. Ps analogues retained antimicrobial activity and exhibited reduced cytotoxicity, whereas Ps-P analogues exhibited lower cytotoxicity and antimicrobial activity. Tertiary structures revealed that Ps has a linear α-helix from Leu2 to Glu24, whereas Ps-P has a bend at Pro11 between two short α-helixes. Using various biophysical experiments, we found that Ps analogues produced much higher membrane depolarization than Ps-P analogues, whereas Ps-P analogues may penetrate bacterial cell membranes. Ps and its analogue Ps-K18 exhibited potent anti-inflammatory activity in LPS-stimulated RAW264.7 and mouse dendritic cells via a mechanism involving the Toll-like receptor 4 (TLR4) pathway. These activities may arise from their direct inhibition of the formation of TLR4-MD-2_LPS complex, implying that amphipathic α-helical structure with an optimum balance between enhanced cationicity and hydrophobicity may be essential for their anti-inflammatory activity. The bent structure provided by Pro substitution plays an important role in enhancing bacterial cell selectivity and cell penetration.Dasom JeonMin-Cheol JeongBinu JacobJeong Kyu BangEun-Hee KimChaejoon CheongIn Duk JungYoonkyung ParkYangmee KimNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-14 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Dasom Jeon Min-Cheol Jeong Binu Jacob Jeong Kyu Bang Eun-Hee Kim Chaejoon Cheong In Duk Jung Yoonkyung Park Yangmee Kim Investigation of cationicity and structure of pseudin-2 analogues for enhanced bacterial selectivity and anti-inflammatory activity
description	Abstract Pseudin-2 (Ps), isolated from the frog Pseudis paradoxa, exhibits potent antibacterial activity and cytotoxicity. To develop antimicrobial peptides with anti-inflammatory activity and low cytotoxicity, we designed Ps analogues with Lys substitutions, resulting in elevated amphipathic α-helical structure and cationicity. We further substituted Gly11 with Pro (Ps-P analogues) to increase bacterial cell selectivity. Ps analogues retained antimicrobial activity and exhibited reduced cytotoxicity, whereas Ps-P analogues exhibited lower cytotoxicity and antimicrobial activity. Tertiary structures revealed that Ps has a linear α-helix from Leu2 to Glu24, whereas Ps-P has a bend at Pro11 between two short α-helixes. Using various biophysical experiments, we found that Ps analogues produced much higher membrane depolarization than Ps-P analogues, whereas Ps-P analogues may penetrate bacterial cell membranes. Ps and its analogue Ps-K18 exhibited potent anti-inflammatory activity in LPS-stimulated RAW264.7 and mouse dendritic cells via a mechanism involving the Toll-like receptor 4 (TLR4) pathway. These activities may arise from their direct inhibition of the formation of TLR4-MD-2_LPS complex, implying that amphipathic α-helical structure with an optimum balance between enhanced cationicity and hydrophobicity may be essential for their anti-inflammatory activity. The bent structure provided by Pro substitution plays an important role in enhancing bacterial cell selectivity and cell penetration.
format	article
author	Dasom Jeon Min-Cheol Jeong Binu Jacob Jeong Kyu Bang Eun-Hee Kim Chaejoon Cheong In Duk Jung Yoonkyung Park Yangmee Kim
author_facet	Dasom Jeon Min-Cheol Jeong Binu Jacob Jeong Kyu Bang Eun-Hee Kim Chaejoon Cheong In Duk Jung Yoonkyung Park Yangmee Kim
author_sort	Dasom Jeon
title	Investigation of cationicity and structure of pseudin-2 analogues for enhanced bacterial selectivity and anti-inflammatory activity
title_short	Investigation of cationicity and structure of pseudin-2 analogues for enhanced bacterial selectivity and anti-inflammatory activity
title_full	Investigation of cationicity and structure of pseudin-2 analogues for enhanced bacterial selectivity and anti-inflammatory activity
title_fullStr	Investigation of cationicity and structure of pseudin-2 analogues for enhanced bacterial selectivity and anti-inflammatory activity
title_full_unstemmed	Investigation of cationicity and structure of pseudin-2 analogues for enhanced bacterial selectivity and anti-inflammatory activity
title_sort	investigation of cationicity and structure of pseudin-2 analogues for enhanced bacterial selectivity and anti-inflammatory activity
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/97a022e25a9a4df2932b8be12cb23e86
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Investigation of cationicity and structure of pseudin-2 analogues for enhanced bacterial selectivity and anti-inflammatory activity

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