The Rational Design of Therapeutic Peptides for Aminopeptidase N using a Substrate-Based Approach

Abstract The M1 family of metalloproteases represents a large number of exopeptidases that cleave single amino acid residues from the N-terminus of peptide substrates. One member of this family that has been well studied is aminopeptidase N (APN), a multifunctional protease known to cleave biologica...

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Autores principales:	Shilvi Joshi, Lang Chen, Michael B. Winter, Yi-Lun Lin, Yang Yang, Mariya Shapovalova, Paige M. Smith, Chang Liu, Fang Li, Aaron M. LeBeau
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/0da13595ddc84cff8dba8adb84bdbdf8
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spelling	oai:doaj.org-article:0da13595ddc84cff8dba8adb84bdbdf82021-12-02T16:06:10ZThe Rational Design of Therapeutic Peptides for Aminopeptidase N using a Substrate-Based Approach10.1038/s41598-017-01542-52045-2322https://doaj.org/article/0da13595ddc84cff8dba8adb84bdbdf82017-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-01542-5https://doaj.org/toc/2045-2322Abstract The M1 family of metalloproteases represents a large number of exopeptidases that cleave single amino acid residues from the N-terminus of peptide substrates. One member of this family that has been well studied is aminopeptidase N (APN), a multifunctional protease known to cleave biologically active peptides and aide in coronavirus entry. The proteolytic activity of APN promotes cancer angiogenesis and metastasis making it an important target for cancer therapy. To understand the substrate specificity of APN for the development of targeted inhibitors, we used a global substrate profiling method to determine the P1–P4′ amino acid preferences. The key structural features of the APN pharmacophore required for substrate recognition were elucidated by x-ray crystallography. By combining these substrate profiling and structural data, we were able to design a selective peptide inhibitor of APN that was an effective therapeutic both in vitro and in vivo against APN-expressing prostate cancer models.Shilvi JoshiLang ChenMichael B. WinterYi-Lun LinYang YangMariya ShapovalovaPaige M. SmithChang LiuFang LiAaron M. LeBeauNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Shilvi Joshi Lang Chen Michael B. Winter Yi-Lun Lin Yang Yang Mariya Shapovalova Paige M. Smith Chang Liu Fang Li Aaron M. LeBeau The Rational Design of Therapeutic Peptides for Aminopeptidase N using a Substrate-Based Approach
description	Abstract The M1 family of metalloproteases represents a large number of exopeptidases that cleave single amino acid residues from the N-terminus of peptide substrates. One member of this family that has been well studied is aminopeptidase N (APN), a multifunctional protease known to cleave biologically active peptides and aide in coronavirus entry. The proteolytic activity of APN promotes cancer angiogenesis and metastasis making it an important target for cancer therapy. To understand the substrate specificity of APN for the development of targeted inhibitors, we used a global substrate profiling method to determine the P1–P4′ amino acid preferences. The key structural features of the APN pharmacophore required for substrate recognition were elucidated by x-ray crystallography. By combining these substrate profiling and structural data, we were able to design a selective peptide inhibitor of APN that was an effective therapeutic both in vitro and in vivo against APN-expressing prostate cancer models.
format	article
author	Shilvi Joshi Lang Chen Michael B. Winter Yi-Lun Lin Yang Yang Mariya Shapovalova Paige M. Smith Chang Liu Fang Li Aaron M. LeBeau
author_facet	Shilvi Joshi Lang Chen Michael B. Winter Yi-Lun Lin Yang Yang Mariya Shapovalova Paige M. Smith Chang Liu Fang Li Aaron M. LeBeau
author_sort	Shilvi Joshi
title	The Rational Design of Therapeutic Peptides for Aminopeptidase N using a Substrate-Based Approach
title_short	The Rational Design of Therapeutic Peptides for Aminopeptidase N using a Substrate-Based Approach
title_full	The Rational Design of Therapeutic Peptides for Aminopeptidase N using a Substrate-Based Approach
title_fullStr	The Rational Design of Therapeutic Peptides for Aminopeptidase N using a Substrate-Based Approach
title_full_unstemmed	The Rational Design of Therapeutic Peptides for Aminopeptidase N using a Substrate-Based Approach
title_sort	rational design of therapeutic peptides for aminopeptidase n using a substrate-based approach
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/0da13595ddc84cff8dba8adb84bdbdf8
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The Rational Design of Therapeutic Peptides for Aminopeptidase N using a Substrate-Based Approach

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