Nizi Emanuela, Sferrazza Alessio, Fabbrini Danilo, Nardi Valentina, Andreini Matteo, Graziani Rita, Gennari Nadia, Bresciani Alberto, Paonessa Giacomo, Harper Steven
Department of Chemistry, IRBM Science Park, Via Pontina km 30, 600, Pomezia 00071, Rome, Italy.
Department of Chemistry, IRBM Science Park, Via Pontina km 30, 600, Pomezia 00071, Rome, Italy.
Bioorg Med Chem Lett. 2018 May 15;28(9):1540-1544. doi: 10.1016/j.bmcl.2018.03.069. Epub 2018 Mar 26.
Falcipain-2 (FP2) is an essential enzyme in the lifecycle of malaria parasites such as Plasmodium falciparum, and its inhibition is viewed as an attractive mechanism of action for new anti-malarial agents. Selective inhibition of FP2 with respect to a family of human cysteine proteases (that include cathepsins B, K, L and S) is likely to be required for the development of agents targeting FP2. Here we describe a series of P2-modified aminonitrile based inhibitors of FP2 that provide a clear strategy toward addressing selectivity for the P. falciparum and show that it can provide potent FP2 inhibitors with strong selectivity against all four of these human cathepsin isoforms.
恶性疟原虫蛋白酶-2（FP2）是恶性疟原虫等疟原虫生命周期中的一种必需酶，对其抑制被视为新型抗疟药物有吸引力的作用机制。开发靶向FP2的药物可能需要对包括组织蛋白酶B、K、L和S在内的一系列人类半胱氨酸蛋白酶实现对FP2的选择性抑制。在此，我们描述了一系列基于P2修饰氨基腈的FP2抑制剂，它们为解决针对恶性疟原虫的选择性提供了明确策略，并表明其能够提供对所有这四种人类组织蛋白酶亚型具有强选择性的高效FP2抑制剂。
