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

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dc.contributor.authorPalasis, K.
dc.contributor.authorPeddie, V.
dc.contributor.authorTurner, D.
dc.contributor.authorZhang, X.
dc.contributor.authorYu, J.
dc.contributor.authorAbell, A.D.
dc.date.issued2023
dc.descriptionFirst published: 16 August 2023
dc.description.abstractThe 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 >5-fold difference in inhibitory activity between isomeric states, whereas the best small molecule inhibitor only showed a 3.4-fold difference. Docking and molecular modelling suggests this result is due to a large change in 3D structure in the key binding residues of the peptidic inhibitor upon isomerisation, which 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.
dc.description.statementofresponsibilityKathryn A. Palasis, Victoria Peddie, Dion J. L. Turner, Xiaozhou Zhang, Jingxian Yu, and Andrew D. Abell
dc.identifier.citationChemBioChem: a European journal of chemical biology, 2023; 24(20):e202300453-1-e202300453-14
dc.identifier.doi10.1002/cbic.202300453
dc.identifier.issn1439-4227
dc.identifier.issn1439-7633
dc.identifier.orcidPalasis, K. [0000-0003-1769-4240]
dc.identifier.orcidTurner, D. [0000-0002-5503-6380]
dc.identifier.orcidYu, J. [0000-0002-6489-5988]
dc.identifier.orcidAbell, A.D. [0000-0002-0604-2629]
dc.identifier.urihttps://hdl.handle.net/2440/139459
dc.language.isoen
dc.publisherWiley
dc.relation.granthttp://purl.org/au-research/grants/arc/CE140100003
dc.rights© 2023 The Authors. ChemBioChem published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
dc.source.urihttps://doi.org/10.1002/cbic.202300453
dc.subjectenzymes
dc.subjectpeptides
dc.subjectphotochemistry
dc.subjectphotoswitches
dc.subjecttrypsin
dc.titleExploring Photoswitchable Binding Interactions with Small Molecule- and Peptide-Based Inhibitors of Trypsin
dc.typeJournal article
pubs.publication-statusPublished

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