Atack Thomas C, Raymond Donald D, Blomquist Christa A, Pasaje Charisse Flerida, McCarren Patrick R, Moroco Jamie, Befekadu Henock B, Robinson Foxy P, Pal Debjani, Esherick Lisl Y, Ianari Alessandra, Niles Jacquin C, Sellers William R
Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, Massachusetts 02142, United States.
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States.
ACS Med Chem Lett. 2020 Sep 1;11(11):2131-2138. doi: 10.1021/acsmedchemlett.0c00272. eCollection 2020 Nov 12.
FK506-binding protein 35, FKBP35, has been implicated as an essential malarial enzyme. Rapamycin and FK506 exhibit antiplasmodium activity in cultured parasites. However, due to the highly conserved nature of the binding pockets of FKBPs and the immunosuppressive properties of these drugs, there is a need for compounds that selectively inhibit FKBP35 and lack the undesired side effects. In contrast to human FKBPs, FKBP35 contains a cysteine, C106, adjacent to the rapamycin binding pocket, providing an opportunity to develop targeted covalent inhibitors of FKBP35. Here, we synthesize inhibitors of FKBP35, show that they directly bind FKBP35 in a model cellular setting, selectively covalently modify C106, and exhibit antiplasmodium activity in blood-stage cultured parasites.
FK506结合蛋白35（FKBP35）被认为是一种重要的疟疾酶。雷帕霉素和FK506在培养的寄生虫中表现出抗疟原虫活性。然而，由于FKBP结合口袋的高度保守性以及这些药物的免疫抑制特性，需要选择性抑制FKBP35且无不良副作用的化合物。与人类FKBP不同，FKBP35在雷帕霉素结合口袋附近含有一个半胱氨酸C106，这为开发FKBP35的靶向共价抑制剂提供了机会。在此，我们合成了FKBP35抑制剂，表明它们在模型细胞环境中直接与FKBP35结合，选择性地共价修饰C106，并在血液阶段培养的寄生虫中表现出抗疟原虫活性。
