The protozoan Plasmodium falciparum is the main aetiological agent of tropical malaria. Characteristic of the phylum is the presence of a plastid-like organelle which hosts several homologs of plant proteins, including a ferredoxin (PfFd) and its NADPH-dependent reductase (PfFNR). The PfFNR/PfFd redox system is essential for the parasite, while mammals share no homologous proteins, making the enzyme an attractive target for novel and much needed antimalarial drugs. Based on previous findings, three chemically reactive residues important for PfFNR activity were identified: namely, the active-site Cys99, responsible for hydride transfer; Cys284, whose oxidation leads to an inactive dimeric form of the protein; and His286, which is involved in NADPH binding. These amino acid residues were probed by several residue-specific reagents and the two cysteines were shown to be promising targets for covalent inhibition. The quantitative and qualitative description of the reactivity of few compounds, including a repurposed drug, set the bases for the development of more potent and specific antimalarial leads.

原生动物恶性疟原虫是热带疟疾的主要病原体。该门的特征是存在质体样细胞器，其承载多种植物蛋白同系物，包括铁氧还蛋白 (PfFd) 及其 NADPH 依赖性还原酶 (PfFNR)。PfFNR/PfFd 氧化还原系统对于寄生虫是必不可少的，而哺乳动物不共享同源蛋白质，这使得该酶成为新型且急需的抗疟药物的有吸引力的目标。基于先前的发现，确定了三个对 PfFNR 活性很重要的化学反应残基：即，负责氢化物转移的活性位点 Cys99；Cys284，其氧化导致蛋白质的无活性二聚体形式；以及参与 NADPH 结合的 His286。这些氨基酸残基被几种残基特异性试剂探测到，这两个半胱氨酸被证明是共价抑制的有希望的靶标。对少数化合物（包括重新利用的药物）反应性的定量和定性描述为开发更有效和更具体的抗疟药物奠定了基础。