Mast Cell Tryptase β as a Target in Allergic Inflammation: An Evolving Story

Abstract

Tryptases comprise a group of trypsin-like serine proteases that are highly and selectively expressed in mast cells and to a lesser extent in basophils. Among them interest has been focused on tryptase beta, primarily because it was the first tryptase identified and because it is the predominant protease and protein component of mast cells. Subsequent studies have provided convincing evidence that tryptase beta is not only a clinically useful marker of mast cells and their activation but that it contributes to the pathogenesis of allergic inflammatory disorders, most notably asthma. The pathogenetic relevance together with the apparent lack of overt physiological functions has caused considerable interest in beta-tryptase as a potential therapeutic target. Meanwhile diverse tryptase inhibitors have been synthesized whose design in part was fostered by the structural analysis of the enzymatically active beta tryptase tetramer. Various compounds have been studied both in animal models and in man, providing proof of principle that tryptase inhibitors have therapeutic potential in asthma. Here we review the rationale to develop tryptase inhibitors and the approaches pursued, and also try to pinpoint some of the problems that hamper the development of clinically applicable drugs.

Is Serum Tryptase a Valuable Marker for Obesity-Bronchial Asthma Interrelationship in Children?

“…This comes in agreement with Sommerhoff and Schaschke [20], who provided a convincing evidence that tryptase B is not only a clinically useful marker of mast cells and their activation but that it contributes to the pathogenesis of allergic infl ammatory disorders, most notably asthma. However serum tryptase levels did not relate to the degree of asthma symptom scores, PEF or FEV1 in study of Taira et al in 2002 [21].…”

Engineered Cystine Knot Miniproteins as Potent Inhibitors of Human Mast Cell Tryptase β

“…Tryptase β thus contributes to the pathogenesis of allergic and inflammatory disorders, most notably asthma and rheumatoid arthritis, and has caused considerable interest in it as a potential drug target. [8][9][10][11] Due to its peculiar molecular architecturehuman tryptase β is active as a heparin-stabilized tetramer [12][13][14] (Fig. 1a), the elucidation of inhibitors acting against tryptase β has focused both on compounds able to bind heparin, thus inactivating the enzyme by tetramer destabilization (e.g., antithrombin II and lactoferrin), 16,17 and on small molecules that can penetrate the central cavity of the tetramer and block the active sites directly.…”

Oxidative Folding and Structural Analyses of a Kunitz-Related Inhibitor and Its Disulfide Intermediates: Functional Implications

“…An in-depth understanding of the folding of such serine protease inhibitors may thus foster the design of variants with improved properties that target, for example, human tryptase β and could alleviate allergic and inflammatory disorders such as asthma and rheumatoid arthritis. 21,56 Materials and Methods…”

“…18 Importantly, TdPI is one of only two proteins identified so far that strongly inhibit human tryptase β, a mast-cell-derived tetrameric serine protease implicated in inflammation and allergy. [19][20][21] This inhibitor consists of 97 residues and contains a Kunitz/BPTI-related domain (55 residues crosslinked by four disulfide bonds) that is surrounded by prehead and posthead segments of 20 and 22 residues, respectively ( Fig. 1).…”