دورية أكاديمية
Covalent inhibition of P. falciparum ferredoxin-NADP + reductase: Exploring alternative strategies for the development of new antimalarial drugs.
| العنوان: | Covalent inhibition of P. falciparum ferredoxin-NADP + reductase: Exploring alternative strategies for the development of new antimalarial drugs. |
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| المؤلفون: | de Rosa M; Istituto di Biofisica, Consiglio Nazionale delle Ricerche, Milano, Italy. Electronic address: matteo.derosa@ibf.cnr.it., Nonnis S; DIMEVET - Dipartimento di Medicina Veterinaria, Università degli Studi di Milano, Milano, Italy; CRC 'Innovation for Well-Beeing and Environment' (I-WE), Università degli Studi di Milano, Milano, Italy., Aliverti A; Dipartimento di Bioscienze, Università degli Studi di Milano, Milano, Italy. |
| المصدر: | Biochemical and biophysical research communications [Biochem Biophys Res Commun] 2021 Nov 05; Vol. 577, pp. 89-94. Date of Electronic Publication: 2021 Sep 04. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier Country of Publication: United States NLM ID: 0372516 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1090-2104 (Electronic) Linking ISSN: 0006291X NLM ISO Abbreviation: Biochem Biophys Res Commun Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: <2002- >: San Diego, CA : Elsevier Original Publication: New York, Academic Press. |
| مواضيع طبية MeSH: | Enzyme Inhibitors/*pharmacology , Ferredoxin-NADP Reductase/*antagonists & inhibitors , Malaria, Falciparum/*prevention & control , Plasmodium falciparum/*drug effects , Protozoan Proteins/*antagonists & inhibitors, Antineoplastic Agents, Alkylating/chemistry ; Antineoplastic Agents, Alkylating/metabolism ; Antineoplastic Agents, Alkylating/pharmacology ; Biocatalysis/drug effects ; Carmustine/chemistry ; Carmustine/metabolism ; Carmustine/pharmacology ; Catalytic Domain ; Cysteine/chemistry ; Cysteine/metabolism ; Diamide/chemistry ; Diamide/metabolism ; Diamide/pharmacology ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/metabolism ; Ferredoxin-NADP Reductase/chemistry ; Ferredoxin-NADP Reductase/metabolism ; Kinetics ; Malaria, Falciparum/parasitology ; Molecular Structure ; NADP/metabolism ; Organomercury Compounds/chemistry ; Organomercury Compounds/metabolism ; Organomercury Compounds/pharmacology ; Plasmodium falciparum/enzymology ; Plasmodium falciparum/physiology ; Protein Binding ; Protein Domains ; Protozoan Proteins/chemistry ; Protozoan Proteins/metabolism ; Substrate Specificity |
| مستخلص: | 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. Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (Copyright © 2021 Elsevier Inc. All rights reserved.) |
| فهرسة مساهمة: | Keywords: Covalent inhibitor; Enzyme kinetics; Ferredoxin; Plasmodium falciparum; Reductase; Tropical malaria |
| المشرفين على المادة: | 0 (Antineoplastic Agents, Alkylating) 0 (Enzyme Inhibitors) 0 (Organomercury Compounds) 0 (Protozoan Proteins) 10465-78-8 (Diamide) 53-59-8 (NADP) EC 1.18.1.2 (Ferredoxin-NADP Reductase) K848JZ4886 (Cysteine) U68WG3173Y (Carmustine) |
| تواريخ الأحداث: | Date Created: 20210911 Date Completed: 20211126 Latest Revision: 20211126 |
| رمز التحديث: | 20240829 |
| DOI: | 10.1016/j.bbrc.2021.09.008 |
| PMID: | 34509083 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1090-2104 |
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| DOI: | 10.1016/j.bbrc.2021.09.008 |