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.
Chembiochem. 2023 Oct 17;24(20):e202300453. doi: 10.1002/cbic.202300453. Epub 2023 Sep 4.
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.
要实现药物的光化学激活，即在需要的时间和地点激活药物，需要优化每种同分异构体之间生物活性的差异。为此，我们报告了基于小分子和肽的同种蛋白酶-胰蛋白酶抑制剂，以更好地了解光可切换药物如何与其生物靶标相互作用。最好的肽抑制剂在同分异构体状态之间表现出超过五倍的抑制活性差异，而最好的小分子抑制剂仅显示出 3.4 倍的差异。对接和分子建模表明，这一结果是由于肽抑制剂在异构化时关键结合残基的 3D 结构发生了很大变化所致；而小分子抑制剂则没有观察到这种情况。因此，我们证明了在照射时关键结合基序中发生显著的结构变化对于最大化同分异构体之间的生物活性差异至关重要。这是未来用于临床应用的光可切换药物设计的一个重要考虑因素。
