Abstract
Tryptase is a serine protease that is released from mast cells during allergic responses. Tryptase inhibitors are being explored as treatments for allergic inflammation in the skin and respiratory system, most notably asthma. Here we report direct tryptase inhibition by natural product compounds. Candidate inhibitors were identified by computational screening of a large (98,000 compounds) virtual library of natural product compounds for tryptase enzymatic site binding. Biochemical assays were used to validate the predicted anti-tryptase activity in vitro, revealing a high (four out of six) success rate for predicting binding using the computational docking model. We further assess tryptase inhibition by a biflavonoid scaffold, whose structure-activity relationship is partially defined by assessing the potency of structurally similar analogs.
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NF, MR, and CG conceived and designed research under guidance from MH. JW performed in silico screening. NF, MR, CG, and SF conducted experiments. NF and MR analyzed data, all of which was generated in-house and no paper mill was used. NF, MR, CG, SF, and MH wrote the manuscript. All authors read and approved the manuscript.
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Fazio, N.F., Russell, M.H., Flinders, S.M. et al. A natural product biflavonoid scaffold with anti-tryptase activity. Naunyn-Schmiedeberg's Arch Pharmacol 394, 107–115 (2021). https://doi.org/10.1007/s00210-020-01959-2
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DOI: https://doi.org/10.1007/s00210-020-01959-2