Cargando…

Rational design peptide inhibitors of Cyclophilin D as a potential treatment for acute pancreatitis

Cyclophilin D (CypD) is a mitochondrial matrix peptidyl prolidase that regulates the mitochondrial permeability transition pore. Inhibition of CypD was suggested as a therapeutic strategy for acute pancreatitis. Peptide inhibitors emerged as novel binding ligand for blocking receptor activity. In th...

Descripción completa

Detalles Bibliográficos
Autores principales: Li, Yuehong, Liu, Ting, Lai, Xiaoyan, Xie, Huifang, Tang, Heng, Wu, Shuangchan, Li, Yongshun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Lippincott Williams & Wilkins 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10695616/
http://dx.doi.org/10.1097/MD.0000000000036188
_version_ 1785153605581406208
author Li, Yuehong
Liu, Ting
Lai, Xiaoyan
Xie, Huifang
Tang, Heng
Wu, Shuangchan
Li, Yongshun
author_facet Li, Yuehong
Liu, Ting
Lai, Xiaoyan
Xie, Huifang
Tang, Heng
Wu, Shuangchan
Li, Yongshun
author_sort Li, Yuehong
collection PubMed
description Cyclophilin D (CypD) is a mitochondrial matrix peptidyl prolidase that regulates the mitochondrial permeability transition pore. Inhibition of CypD was suggested as a therapeutic strategy for acute pancreatitis. Peptide inhibitors emerged as novel binding ligand for blocking receptor activity. In this study, we present our computational approach for designing peptide inhibitors of CypD. The 3-D structure of random peptides were built, and docked into the active center of CypD using Rosetta script integrated FlexPepDock module. The peptide displayed the lowest binding energy against CypD was further selected for virtual iterative mutation based on virtual mutagenesis and molecular docking. Finally, the top 5 peptides with the lowest binding energy was selected for validating their affinity against CypD using inhibitory assay. We showed 4 out of the selected 5 peptides were capable for blocking the activity of CypD, while WACLQ display the strongest affinity against CypD, which reached 0.28 mM. The binding mechanism between WACLQ and CypD was characterized using molecular dynamics simulation. Here, we proved our approach can be a robust method for screening peptide inhibitors.
format Online
Article
Text
id pubmed-10695616
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher Lippincott Williams & Wilkins
record_format MEDLINE/PubMed
spelling pubmed-106956162023-12-05 Rational design peptide inhibitors of Cyclophilin D as a potential treatment for acute pancreatitis Li, Yuehong Liu, Ting Lai, Xiaoyan Xie, Huifang Tang, Heng Wu, Shuangchan Li, Yongshun Medicine (Baltimore) 3800 Cyclophilin D (CypD) is a mitochondrial matrix peptidyl prolidase that regulates the mitochondrial permeability transition pore. Inhibition of CypD was suggested as a therapeutic strategy for acute pancreatitis. Peptide inhibitors emerged as novel binding ligand for blocking receptor activity. In this study, we present our computational approach for designing peptide inhibitors of CypD. The 3-D structure of random peptides were built, and docked into the active center of CypD using Rosetta script integrated FlexPepDock module. The peptide displayed the lowest binding energy against CypD was further selected for virtual iterative mutation based on virtual mutagenesis and molecular docking. Finally, the top 5 peptides with the lowest binding energy was selected for validating their affinity against CypD using inhibitory assay. We showed 4 out of the selected 5 peptides were capable for blocking the activity of CypD, while WACLQ display the strongest affinity against CypD, which reached 0.28 mM. The binding mechanism between WACLQ and CypD was characterized using molecular dynamics simulation. Here, we proved our approach can be a robust method for screening peptide inhibitors. Lippincott Williams & Wilkins 2023-12-01 /pmc/articles/PMC10695616/ http://dx.doi.org/10.1097/MD.0000000000036188 Text en Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc. https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY) (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle 3800
Li, Yuehong
Liu, Ting
Lai, Xiaoyan
Xie, Huifang
Tang, Heng
Wu, Shuangchan
Li, Yongshun
Rational design peptide inhibitors of Cyclophilin D as a potential treatment for acute pancreatitis
title Rational design peptide inhibitors of Cyclophilin D as a potential treatment for acute pancreatitis
title_full Rational design peptide inhibitors of Cyclophilin D as a potential treatment for acute pancreatitis
title_fullStr Rational design peptide inhibitors of Cyclophilin D as a potential treatment for acute pancreatitis
title_full_unstemmed Rational design peptide inhibitors of Cyclophilin D as a potential treatment for acute pancreatitis
title_short Rational design peptide inhibitors of Cyclophilin D as a potential treatment for acute pancreatitis
title_sort rational design peptide inhibitors of cyclophilin d as a potential treatment for acute pancreatitis
topic 3800
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10695616/
http://dx.doi.org/10.1097/MD.0000000000036188
work_keys_str_mv AT liyuehong rationaldesignpeptideinhibitorsofcyclophilindasapotentialtreatmentforacutepancreatitis
AT liuting rationaldesignpeptideinhibitorsofcyclophilindasapotentialtreatmentforacutepancreatitis
AT laixiaoyan rationaldesignpeptideinhibitorsofcyclophilindasapotentialtreatmentforacutepancreatitis
AT xiehuifang rationaldesignpeptideinhibitorsofcyclophilindasapotentialtreatmentforacutepancreatitis
AT tangheng rationaldesignpeptideinhibitorsofcyclophilindasapotentialtreatmentforacutepancreatitis
AT wushuangchan rationaldesignpeptideinhibitorsofcyclophilindasapotentialtreatmentforacutepancreatitis
AT liyongshun rationaldesignpeptideinhibitorsofcyclophilindasapotentialtreatmentforacutepancreatitis