Lysine targeting covalent inhibitors of malarial kinase PfCLK3†

IF 3.6 4区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Skye B. Brettell, Gillian Cann, Abbey Begen, Saumya Sharma, Amit Mahindra, Lauren V. Carruthers, Graeme Milligan, David J. Clarke, Andrew B. Tobin and Andrew G. Jamieson
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Abstract

Malaria continues to devastate tropical regions of the world, with resistance to frontline drugs on the rise. Kinase inhibition has emerged as a promising novel mechanism of action in the fight against malaria. We previously reported the development of TCMDC-135051 (1), a highly potent, multi-stage inhibitor of Plasmodium falciparum CLK3 (PfCLK3). Building on this work, we subsequently developed the first covalent kinase inhibitor for malaria, selectively targeting a unique cysteine residue. Despite their high potency and selectivity, covalent inhibitors that target cysteine residues are particularly vulnerable to resistance arising from single point mutations of the nucleophilic residue. This work presents a novel strategy targeting the essential kinase catalytic lysine residue which has the potential to evade this resistance mechanism. Using structure based drug design, analogues of TCMDC-135051 (1) targeting Lys394 of PfCLK3 were developed. Four compounds, all harbouring benzaldehyde-based warheads, covalently engaged Lys394 as determined by protein mass spectrometry. These analogues were highly potent against recombinant protein, with good parasiticidal potency and cytotoxicity profiles. These molecules 4, 5, 8, 9 are the first lysine-targeting covalent inhibitors reported for malaria and offer a promising general strategy for future antimalarial drug discovery.

Abstract Image

赖氨酸靶向疟疾激酶PfCLK3共价抑制剂。
疟疾继续在世界热带地区肆虐,对一线药物的耐药性正在上升。激酶抑制已成为对抗疟疾的一种有希望的新作用机制。我们之前报道了TCMDC-135051(1)的开发,这是一种高效的恶性疟原虫CLK3 (PfCLK3)多期抑制剂。在这项工作的基础上,我们随后开发了第一个用于疟疾的共价激酶抑制剂,选择性地靶向一种独特的半胱氨酸残基。尽管它们具有高效力和选择性,但针对半胱氨酸残基的共价抑制剂特别容易受到亲核残基单点突变引起的耐药性的影响。本研究提出了一种针对必需激酶催化赖氨酸残基的新策略,该策略有可能逃避这种抗性机制。采用基于结构的药物设计,开发了靶向PfCLK3 Lys394的TCMDC-135051(1)的类似物。通过蛋白质质谱测定,四种化合物都含有苯甲醛基弹头,共价与Lys394结合。这些类似物对重组蛋白具有很强的抗寄生能力和细胞毒性。这些分子4、5、8、9是首次报道的针对赖氨酸的疟疾共价抑制剂,为未来发现抗疟疾药物提供了一个有希望的总体策略。
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来源期刊
CiteScore
5.80
自引率
2.40%
发文量
129
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