Exploring Photoswitchable Binding Interactions with Small-Molecule- and Peptide-Based Inhibitors of Trypsin.

Trypsin / metabolism Models, Molecular Peptides / pharmacology Peptides, Cyclic / chemistry Trypsin Inhibitors / pharmacology
enzymes peptides photochemistry photoswitches trypsin

Journal

Chembiochem : a European journal of chemical biology
ISSN: 1439-7633
Titre abrégé: Chembiochem
Pays: Germany
ID NLM: 100937360

Informations de publication

Date de publication:
17 10 2023
Historique:
revised: 13 08 2023
received: 18 06 2023
medline: 23 10 2023
pubmed: 16 8 2023
entrez: 16 8 2023
Statut: ppublish

Résumé

The ability to photochemically activate a drug, both when and where needed, requires optimisation of the difference in biological activity between each isomeric state. As a step to this goal, we report small-molecule- and peptide-based inhibitors of the same protease-trypsin-to better understand how photoswitchable drugs interact with their biological target. The best peptidic inhibitor displayed a more than fivefold difference in inhibitory activity between isomeric states, whereas the best small-molecule inhibitor only showed a 3.4-fold difference. Docking and molecular modelling suggest this result is due to a large change in 3D structure in the key binding residues of the peptidic inhibitor upon isomerisation; this is not observed for the small-molecule inhibitor. Hence, we demonstrate that significant structural changes in critical binding motifs upon irradiation are essential for maximising the difference in biological activity between isomeric states. This is an important consideration in the design of future photoswitchable drugs for clinical applications.

Identifiants

DOI: 10.1002/cbic.202300453 PMID: 37584529
pubmed: 37584529
doi: 10.1002/cbic.202300453
doi:

Substances chimiques

Trypsin EC 3.4.21.4
Peptides 0
Peptides, Cyclic 0
Trypsin Inhibitors 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

e202300453

Informations de copyright

© 2023 The Authors. ChemBioChem published by Wiley-VCH GmbH.

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Auteurs

Kathryn A Palasis (KA)

ARC Centre of Excellence for Nanoscale BioPhotonics (CNBP), Institute for Photonics and Advanced Sensing (IPAS), Department of Chemistry, The University of Adelaide, North Terrace, Adelaide, SA 5005, Australia.

Victoria Peddie (V)

ARC Centre of Excellence for Nanoscale BioPhotonics (CNBP), Institute for Photonics and Advanced Sensing (IPAS), Department of Chemistry, The University of Adelaide, North Terrace, Adelaide, SA 5005, Australia.

Dion J L Turner (DJL)

ARC Centre of Excellence for Nanoscale BioPhotonics (CNBP), Institute for Photonics and Advanced Sensing (IPAS), Department of Chemistry, The University of Adelaide, North Terrace, Adelaide, SA 5005, Australia.

Xiaozhou Zhang (X)

ARC Centre of Excellence for Nanoscale BioPhotonics (CNBP), Institute for Photonics and Advanced Sensing (IPAS), Department of Chemistry, The University of Adelaide, North Terrace, Adelaide, SA 5005, Australia.

Jingxian Yu (J)

ARC Centre of Excellence for Nanoscale BioPhotonics (CNBP), Institute for Photonics and Advanced Sensing (IPAS), Department of Chemistry, The University of Adelaide, North Terrace, Adelaide, SA 5005, Australia.
Guangxi Key Laboratory of Electrochemical and, Magneto-chemical Functional Materials, College of Chemistry and Bioengineering, Guilin University of Technology, Guilin, 541004, P. R. China.

Andrew D Abell (AD)

ARC Centre of Excellence for Nanoscale BioPhotonics (CNBP), Institute for Photonics and Advanced Sensing (IPAS), Department of Chemistry, The University of Adelaide, North Terrace, Adelaide, SA 5005, Australia.
ORCID: 0000-0002-0604-2629

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Classifications MeSH

questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Hydrolases › Peptide hydrolases › Protéases à sérine › Serine endopeptidases › Trypsine › Exploring Photoswitchable Binding Interactions...
questionsmedicales.fr › Techniques d'investigation › Modèles théoriques › Modèles moléculaires › Exploring Photoswitchable Binding Interactions...
questionsmedicales.fr › Acides aminés, peptides et protéines › Peptides › Exploring Photoswitchable Binding Interactions...
questionsmedicales.fr › Acides aminés, peptides et protéines › Peptides › Peptides cycliques › Exploring Photoswitchable Binding Interactions...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Mécanismes moléculaires de l'action pharmacologique › Antienzymes › Inhibiteurs de protéases › Inhibiteurs de la sérine protéinase › Inhibiteurs trypsiques › Exploring Photoswitchable Binding Interactions...