Targeting <i>Pf</i>CLK3 with Covalent Inhibitors:\nA Novel Strategy for Malaria Treatment

Malaria still causes over 600,000 deaths annually, with\nrising\nresistance to frontline drugs by Plasmodium falciparum increasing this number each year. New medicines with novel mechanisms\nof action are, therefore, urgently needed. In this work, we solved\nthe cocrystal structure of the essential malarial kinase <i>Pf</i>CLK3 with the reversible inhibitor TCMDC-135051 (<b>1</b>),\nenabling the design of covalent inhibitors targeting a unique cysteine\nresidue (Cys368) poorly conserved in the human kinome. Chloroacetamide <b>4</b> shows nanomolar potency and covalent inhibition in both\nrecombinant protein and P. falciparum assays. Efficacy in parasites persisted after a 6 h washout, indicating\nan extended duration of action. Additionally, <b>4</b> showed\nimproved kinase selectivity and a high selectivity index against HepG2\ncells, with a low propensity for resistance (log MIR > 8.1). To\nour\nknowledge, compound <b>4</b> is the first covalent inhibitor\nof a malarial kinase, offering promising potential as a lead for a\nsingle-dose malaria cure.