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Ranacyclin-NF, a Novel Bowman–Birk Type Protease Inhibitor from the Skin Secretion of the East Asian Frog, Pelophylax nigromaculatus

Serine protease inhibitors are found in plants, animals and microorganisms, where they play important roles in many physiological and pathological processes. Inhibitor scaffolds based on natural proteins and peptides have gradually become the focus of current research as they tend to bind to their t...

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Autores principales: Wang, Tao, Jiang, Yangyang, Chen, Xiaoling, Wang, Lei, Ma, Chengbang, Xi, Xinping, Zhang, Yingqi, Chen, Tianbao, Shaw, Chris, Zhou, Mei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7407945/
https://www.ncbi.nlm.nih.gov/pubmed/32630758
http://dx.doi.org/10.3390/biology9070149
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author Wang, Tao
Jiang, Yangyang
Chen, Xiaoling
Wang, Lei
Ma, Chengbang
Xi, Xinping
Zhang, Yingqi
Chen, Tianbao
Shaw, Chris
Zhou, Mei
author_facet Wang, Tao
Jiang, Yangyang
Chen, Xiaoling
Wang, Lei
Ma, Chengbang
Xi, Xinping
Zhang, Yingqi
Chen, Tianbao
Shaw, Chris
Zhou, Mei
author_sort Wang, Tao
collection PubMed
description Serine protease inhibitors are found in plants, animals and microorganisms, where they play important roles in many physiological and pathological processes. Inhibitor scaffolds based on natural proteins and peptides have gradually become the focus of current research as they tend to bind to their targets with greater specificity than small molecules. In this report, a novel Bowman–Birk type inhibitor, named ranacyclin-NF (RNF), is described and was identified in the skin secretion of the East Asian frog, Pelophylax nigromaculatus. A synthetic replicate of the peptide was subjected to a series of functional assays. It displayed trypsin inhibitory activity with an inhibitory constant, Ki, of 447 nM and had negligible direct cytotoxicity. No observable direct antimicrobial activity was found but RNF improved the therapeutic potency of Gentamicin against Methicillin-resistant Staphylococcus aureus (MRSA). RNF shared significant sequence similarity to previously reported and related inhibitors from Odorrana grahami (ORB) and Rana esculenta (ranacyclin-T), both of which were found to be multi-functional. Two analogues of RNF, named ranacyclin-NF1 (RNF1) and ranacyclin-NF3L (RNF3L), were designed based on some features of ORB and ranacyclin-T to study structure–activity relationships. Structure–activity studies demonstrated that residues outside of the trypsin inhibitory loop (TIL) may be related to the efficacy of trypsin inhibitory activity.
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spelling pubmed-74079452020-08-12 Ranacyclin-NF, a Novel Bowman–Birk Type Protease Inhibitor from the Skin Secretion of the East Asian Frog, Pelophylax nigromaculatus Wang, Tao Jiang, Yangyang Chen, Xiaoling Wang, Lei Ma, Chengbang Xi, Xinping Zhang, Yingqi Chen, Tianbao Shaw, Chris Zhou, Mei Biology (Basel) Article Serine protease inhibitors are found in plants, animals and microorganisms, where they play important roles in many physiological and pathological processes. Inhibitor scaffolds based on natural proteins and peptides have gradually become the focus of current research as they tend to bind to their targets with greater specificity than small molecules. In this report, a novel Bowman–Birk type inhibitor, named ranacyclin-NF (RNF), is described and was identified in the skin secretion of the East Asian frog, Pelophylax nigromaculatus. A synthetic replicate of the peptide was subjected to a series of functional assays. It displayed trypsin inhibitory activity with an inhibitory constant, Ki, of 447 nM and had negligible direct cytotoxicity. No observable direct antimicrobial activity was found but RNF improved the therapeutic potency of Gentamicin against Methicillin-resistant Staphylococcus aureus (MRSA). RNF shared significant sequence similarity to previously reported and related inhibitors from Odorrana grahami (ORB) and Rana esculenta (ranacyclin-T), both of which were found to be multi-functional. Two analogues of RNF, named ranacyclin-NF1 (RNF1) and ranacyclin-NF3L (RNF3L), were designed based on some features of ORB and ranacyclin-T to study structure–activity relationships. Structure–activity studies demonstrated that residues outside of the trypsin inhibitory loop (TIL) may be related to the efficacy of trypsin inhibitory activity. MDPI 2020-07-02 /pmc/articles/PMC7407945/ /pubmed/32630758 http://dx.doi.org/10.3390/biology9070149 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Wang, Tao
Jiang, Yangyang
Chen, Xiaoling
Wang, Lei
Ma, Chengbang
Xi, Xinping
Zhang, Yingqi
Chen, Tianbao
Shaw, Chris
Zhou, Mei
Ranacyclin-NF, a Novel Bowman–Birk Type Protease Inhibitor from the Skin Secretion of the East Asian Frog, Pelophylax nigromaculatus
title Ranacyclin-NF, a Novel Bowman–Birk Type Protease Inhibitor from the Skin Secretion of the East Asian Frog, Pelophylax nigromaculatus
title_full Ranacyclin-NF, a Novel Bowman–Birk Type Protease Inhibitor from the Skin Secretion of the East Asian Frog, Pelophylax nigromaculatus
title_fullStr Ranacyclin-NF, a Novel Bowman–Birk Type Protease Inhibitor from the Skin Secretion of the East Asian Frog, Pelophylax nigromaculatus
title_full_unstemmed Ranacyclin-NF, a Novel Bowman–Birk Type Protease Inhibitor from the Skin Secretion of the East Asian Frog, Pelophylax nigromaculatus
title_short Ranacyclin-NF, a Novel Bowman–Birk Type Protease Inhibitor from the Skin Secretion of the East Asian Frog, Pelophylax nigromaculatus
title_sort ranacyclin-nf, a novel bowman–birk type protease inhibitor from the skin secretion of the east asian frog, pelophylax nigromaculatus
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7407945/
https://www.ncbi.nlm.nih.gov/pubmed/32630758
http://dx.doi.org/10.3390/biology9070149
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