In combination therapies against malaria, artemisinins are currently the most effective drugs used. Although the subject of intense research for many years, artemisinin's molecular mechanism of action remains a topic of debate.
A much clearer picture of how this compound class works would provide crucial information in the effort to create more effective antimalarial drugs that are less susceptible to resistance. A conventional model suggests that artemisinin elicits its effects through the formation of heme-derived FeII and C-centered radicals. However, a research project led by Richard K. Haynes and Diego Monti has provided strong evidence to counter this model, and their results are reported in the journal ChemMedChem.
"Our research reveals completely new chemistry that includes the formation of unexpected products and which is coherent with relevant enzyme assays," says Haynes. "It directs the science away from the FeII activation theory that is universally held to underpin the antimalarial action of artemisinins. The lead into this work was the use of methylene blue (MB) as an antimalarial drug and the synergistic effect it displays with artemisinins. This is compatible with the idea that artemisinins, like MB, are redox-active molecules that interfere with redox enzymes important for the malaria parasite. MB is converted by reduced flavin cofactors into leucomethylene blue, which initiates a redox cycle involving molecular oxygen. We therefore examined the behavior of such reduced cofactors and model compounds with artemisinins. Importantly, we were able to generate the reduced cofactors catalytically in neutral aqueous (biologically relevant) buffer in the presence of artemisinin and biological reductants, the latter of which alone do not affect the artemisinins. In this sense, our work differs from virtually every other chemical/mechanistic study that has been carried out to date. We report that artemisinins are able to undergo both one-electron transfer and two-electron reduction, and both sets of reactions must have biological consequences."
As for the next step in this project, Haynes and Monti indicate that "Whilst we have not yet tried to pinpoint the flavin cofactor of any particular intra-parasitic enzyme that may be targeted, it is apparent that several flavoenzymes are susceptible to artemisinins. Detailed biochemical and kinetic investigations are being conducted in follow-up studies."
Author: Richard K. Haynes, The Hong Kong University of Science and Technology (China), http://www-chem.ust.hk/Faculty%20staff/Haynes/content.htm
Title: Facile Oxidation of Leucomethylene Blue and Dihydroflavins by Artemisinins: Relationship with Flavoenzyme Function and Antimalarial Mechanism of Action
ChemMedChem 2010, 5, No. 8, 1282–1299, Permalink to the article: http://dx.doi.org/10.1002/cmdc.201000225
Richard K. Haynes | Wiley-VCH
Cancer diagnosis: no more needles?
25.05.2018 | Christian-Albrechts-Universität zu Kiel
Less is more? Gene switch for healthy aging found
25.05.2018 | Leibniz-Institut für Alternsforschung - Fritz-Lipmann-Institut e.V. (FLI)
The more electronics steer, accelerate and brake cars, the more important it is to protect them against cyber-attacks. That is why 15 partners from industry and academia will work together over the next three years on new approaches to IT security in self-driving cars. The joint project goes by the name Security For Connected, Autonomous Cars (SecForCARs) and has funding of €7.2 million from the German Federal Ministry of Education and Research. Infineon is leading the project.
Vehicles already offer diverse communication interfaces and more and more automated functions, such as distance and lane-keeping assist systems. At the same...
A research team led by physicists at the Technical University of Munich (TUM) has developed molecular nanoswitches that can be toggled between two structurally different states using an applied voltage. They can serve as the basis for a pioneering class of devices that could replace silicon-based components with organic molecules.
The development of new electronic technologies drives the incessant reduction of functional component sizes. In the context of an international collaborative...
At the LASYS 2018, from June 5th to 7th, the Laser Zentrum Hannover e.V. (LZH) will be showcasing processes for the laser material processing of tomorrow in hall 4 at stand 4E75. With blown bomb shells the LZH will present first results of a research project on civil security.
At this year's LASYS, the LZH will exhibit light-based processes such as cutting, welding, ablation and structuring as well as additive manufacturing for...
There are videos on the internet that can make one marvel at technology. For example, a smartphone is casually bent around the arm or a thin-film display is rolled in all directions and with almost every diameter. From the user's point of view, this looks fantastic. From a professional point of view, however, the question arises: Is that already possible?
At Display Week 2018, scientists from the Fraunhofer Institute for Applied Polymer Research IAP will be demonstrating today’s technological possibilities and...
So-called quantum many-body scars allow quantum systems to stay out of equilibrium much longer, explaining experiment | Study published in Nature Physics
Recently, researchers from Harvard and MIT succeeded in trapping a record 53 atoms and individually controlling their quantum state, realizing what is called a...
25.05.2018 | Event News
02.05.2018 | Event News
13.04.2018 | Event News
25.05.2018 | Event News
25.05.2018 | Machine Engineering
25.05.2018 | Life Sciences