A natural product biflavonoid scaffold with anti-tryptase activity
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ORIGINAL ARTICLE
A natural product biflavonoid scaffold with anti-tryptase activity Nicholas F. Fazio 1 & Michael H. Russell 1 & Steven M. Flinders 1 & Colin J. Gardner 1 & Jace B. Webster 1 & Marc D.H. Hansen 1 Received: 8 January 2020 / Accepted: 3 August 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
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. Keywords Tryptase . Mast cell . Computational screen . Biflavonoid
Introduction Mast cells function in immune responses to external antigens. Of hematopoietic origin, mast cells populate vascularized tissues, especially mucosal and epithelial layers of the gastrointestinal tract, skin, and respiratory tract (Krystel-Whittemore et al. 2015). Mast cells are activated by many triggers, resulting in release of inflammatory molecules stored in large cytoplasmic granules (da Silva et al. 2014). Granule contents include histamine, heparin, various cytokines, chondroitin sulfate, and, most abundantly, neutral proteases (da Silva et al. 2014). Neutral protease expression in mast cells varies by location; while connective tissue mast cells produce tryptase, chymase, and carboxytryptase, mucosal mast cells primarily produce tryptase (Irani et al. 1986). Tryptase activates protease-activated receptor type 2 (PAR2) to initiate and amplify the immune response (Liedtke and Heller 2007). Mast cell progenitors are recruited to sites of tryptase release, predisposing the site to enhanced Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00210-020-01959-2) contains supplementary material, which is available to authorized users. * Marc D.H. Hansen [email protected] 1
Department of Physiology and Developmental Biology, Brigham Young University, 4005 LSB, Provo, UT 84602, USA
inflammation in response to certain external stimuli (Collington et al. 2011). Thus, tryptase participates in normal physiological processes, such as airway homeostasis, vascular relaxation, and contraction, and also drives pathological inflammatory processes, such as allergic reactions, mastocytosis, and some hematological conditions (Payne and Kam 2004). A number of tryptase inhibitors have been developed as potential therapeutics. Anticoagulant ser
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