Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Via P. Giuria 9, 10125, Torino, Italy.
Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Via P. Giuria 9, 10125, Torino, Italy.
Arch Biochem Biophys. 2019 Jul 30;670:116-139. doi: 10.1016/j.abb.2018.11.013. Epub 2018 Nov 16.
The NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome is the best recognized and most widely implicated regulator of caspase-1 activation. It is a key regulator of innate immune response and is involved in many pathophysiological processes. Recent evidences for its inappropriate activation in autoinflammatory, autoimmune, as well as in neurodegenerative diseases attract a growing interest toward the development of small molecules NLRP3 inhibitors. Based on the knowledge of biochemical and structural aspects of NLRP3 activation, one successful strategy in the identification of NLRP3 inhibitors relies on the development of covalent irreversible inhibitors. Covalent inhibitors are reactive electrophilic molecules able to alkylate nucleophiles in the target protein. These inhibitors could ensure good efficacy and prolonged duration of action both in vitro and in vivo. In spite of these advantages, effects on other signalling pathways, prone to alkylation, may occur. In this review, we will illustrate the chemistry and the biological action of the most studied covalent NLRP3 inhibitors developed so far. A description of what we know about their mechanism of action will address the reader toward a critical understanding of NLRP3 inhibition by electrophilic compounds.
NOD 样受体家族，含 pyrin 域蛋白 3（NLRP3）炎症小体是目前公认的、最广泛涉及 caspase-1 激活的调节因子。它是先天免疫反应的关键调节剂，参与许多病理生理过程。最近有证据表明，它在自身炎症性、自身免疫性和神经退行性疾病中的异常激活引起了人们对小分子 NLRP3 抑制剂的开发越来越感兴趣。基于 NLRP3 激活的生化和结构方面的知识，鉴定 NLRP3 抑制剂的一种成功策略依赖于开发共价不可逆抑制剂。共价抑制剂是能够烷基化靶蛋白中亲核试剂的反应性亲电分子。这些抑制剂可以确保在体外和体内都具有良好的疗效和持久的作用。尽管有这些优势，但可能会对其他易被烷基化的信号通路产生影响。在这篇综述中，我们将阐述迄今为止开发的最具研究价值的共价 NLRP3 抑制剂的化学和生物学作用。对其作用机制的描述将使读者能够批判性地理解亲电化合物对 NLRP3 的抑制作用。
