N-89, a new antimalarial endoperoxide, was selected as a promising antimalarial compound showing high activity and selectivity. To study the mechanism of N-89 action, N-89 resistant strain (NRC10) was obtained by intermittent drug pressure. NRC10 had a tenfold increase in the EC(50) value of N-89. No cross-resistance was obtained with other antimalarial compounds. Comparative proteome analysis of N-89 sensitive and NRC10 strains revealed over-expression of 12 spots and down-regulation of 14 spots in NRC10. Fifteen proteins were identified of Plasmodium falciparum origin. The identified proteins representing several functions, mainly related to the glycolytic pathway, and metabolism of protein and lipid. Our results suggest that identified proteins may be candidates of antimalarial endoperoxide targets.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1007/s00436-007-0460-8 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
The antimalarial activity of transdermal N-89 mediated by inhibiting ERC gene expression in P. Berghei-infected mice.
Parasitol Int
December 2024
Division of International Infectious Diseases Control, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8530, Japan. Electronic address:
Through studies of new antimalarial drugs, we identified 1,2,6,7-tetraoxaspiro[7.11]nonadecane (N-89) as a potential drug candidate. Here, we analyzed the antimalarial action of a transdermal formulation (td) of N-89, designed for easy use by children, using Plasmodium berghei-infected mice as a model for malaria patients.
View Article and Find Full Text PDFReductive Activation of Artefenomel (OZ439) by Fe(II)-Heme, Related to Its Antimalarial Activity.
ACS Infect Dis
January 2025
Laboratoire de Chimie de Coordination du CNRS, LCC-CNRS, 205 route de Narbonne, 31077 Toulouse Cedex 4, France.
The 1,2,4-trioxolane antimalarial drug, OZ439 (artefenomel), exhibits cross-resistance to artemisinins with similar survival rates of artemisinin-resistant parasites after dihydroartemisinin or OZ439 exposure, suggesting that this drug shares some mechanisms of action with artemisinins. In this way, we investigated the reductive activation of OZ439 by heme in the presence of dithionite, demonstrating the formation of covalent heme-drug adducts. However, in the presence of the biologically abundant reductant glutathione instead of dithionite, heme-drug adducts were not detected, contrary to artemisinin that efficiently alkylates heme regardless of the reductant used.
View Article and Find Full Text PDFArtemisinin-resistant Plasmodium falciparum Kelch13 mutant proteins display reduced heme-binding affinity and decreased artemisinin activation.
Commun Biol
November 2024
Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi, Delhi, 110067, India.
The potency of frontline antimalarial drug artemisinin (ART) derivatives is triggered by heme-induced cleavage of the endoperoxide bond to form reactive heme-ART alkoxy radicals and covalent heme-ART adducts, which are highly toxic to the parasite. ART-resistant (ART-R) parasites with mutations in the Plasmodium falciparum Kelch-containing protein Kelch13 (PfKekch13) exhibit impaired hemoglobin uptake, reduced yield of hemoglobin-derived heme, and thus decreased ART activation. However, any direct involvement of PfKelch13 in heme-mediated ART activation has not been reported.
View Article and Find Full Text PDFNovel frontiers through nitrogen substitution at 6th, 10th and 11th position of artemisinin: Synthetic approaches and antimalarial activity.
Eur J Med Chem
January 2025
Department of Chemistry, Banasthali University, Banasthali Newai, 304022, Rajasthan, India; Department of Education in Science and Mathematics (DESM), Regional Institute of Education (NCERT), Bhubaneshwar, 751022, India. Electronic address:
Malaria pertains to an array of catastrophic illnesses spurred on by the Plasmodium spp. Artemisinin (ART) is currently prescribed in conjunction with another medication as part of therapeutic regimens for acute malaria. These currently prescribed pharmaceuticals have been around for a while, even after lack of required thermos-metabolic stabilities, alongside fresh proclaims about surfacing resistance and neurotoxicity linked with sequential administration of such combination therapies.
View Article and Find Full Text PDFSearching for the Holy Grail - Highly Potent Bridged Endoperoxides for Targeted Cancer Therapy.
Bioorg Chem
December 2024
Chair and Department of Chemical Technology of Drugs, Poznan University of Medical Sciences, ul. Rokietnicka 3, 60-806, Poznań, Poland.
The International Agency for Research on Cancer (IARC) recently estimated the global cancer burden in 2050. The statistics are startling, with a 77% hike and 35 million new cancer cases per year. The present discoveries have recommended plant-derived bridged endoperoxides or artemisinin-based semisynthetic analogues as safe, well-tolerated and powerful substitutes that could be effectively utilized as a warhead to fight against global enemies like cancer.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!