Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy.
Department of Biotechnology, Chemistry and Pharmacy, DoE Department of Excellence 2018-2022, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy.
Molecules. 2022 Apr 15;27(8):2561. doi: 10.3390/molecules27082561.
In the field of drug discovery, the nitrile group is well represented among drugs and biologically active compounds. It can form both non-covalent and covalent interactions with diverse biological targets, and it is amenable as an electrophilic warhead for covalent inhibition. The main advantage of the nitrile group as a warhead is mainly due to its milder electrophilic character relative to other more reactive groups (e.g., -CHO), reducing the possibility of unwanted reactions that would hinder the development of safe drugs, coupled to the ease of installation through different synthetic approaches. The covalent inhibition is a well-assessed design approach for serine, threonine, and cysteine protease inhibitors. The mechanism of hydrolysis of these enzymes involves the formation of a covalent acyl intermediate, and this mechanism can be exploited by introducing electrophilic warheads in order to mimic this covalent intermediate. Due to the relevant role played by the cysteine protease in the survival and replication of infective agents, spanning from viruses to protozoan parasites, we will review the most relevant and recent examples of protease inhibitors presenting a nitrile group that have been introduced to form or to facilitate the formation of a covalent bond with the catalytic cysteine active site residue.
在药物发现领域，腈基在药物和具有生物活性的化合物中广泛存在。它可以与各种生物靶标形成非共价和共价相互作用，并且可以作为共价抑制的亲电弹头。腈基作为弹头的主要优点主要归因于其相对于其他更具反应性的基团（例如 -CHO）的较温和的亲电性，降低了阻碍安全药物开发的不必要反应的可能性，加上通过不同合成方法安装的容易性。共价抑制是丝氨酸、苏氨酸和半胱氨酸蛋白酶抑制剂的一种经过充分评估的设计方法。这些酶的水解机制涉及形成共价酰基中间体，并且可以通过引入亲电弹头来利用这种机制，以模拟这种共价中间体。由于半胱氨酸蛋白酶在感染性剂的存活和复制中发挥着相关作用，从病毒到原生动物寄生虫，我们将综述带有腈基的蛋白酶抑制剂的最新和最相关的实例，这些抑制剂被引入以形成或促进与催化半胱氨酸活性位点残基形成共价键。
