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
Zap! Graphene is bad news for bacteria
23.05.2017 | Rice University
Discovery of an alga's 'dictionary of genes' could lead to advances in biofuels, medicine
23.05.2017 | University of California - Los Angeles
An international team of physicists has monitored the scattering behaviour of electrons in a non-conducting material in real-time. Their insights could be beneficial for radiotherapy.
We can refer to electrons in non-conducting materials as ‘sluggish’. Typically, they remain fixed in a location, deep inside an atomic composite. It is hence...
Two-dimensional magnetic structures are regarded as a promising material for new types of data storage, since the magnetic properties of individual molecular building blocks can be investigated and modified. For the first time, researchers have now produced a wafer-thin ferrimagnet, in which molecules with different magnetic centers arrange themselves on a gold surface to form a checkerboard pattern. Scientists at the Swiss Nanoscience Institute at the University of Basel and the Paul Scherrer Institute published their findings in the journal Nature Communications.
Ferrimagnets are composed of two centers which are magnetized at different strengths and point in opposing directions. Two-dimensional, quasi-flat ferrimagnets...
An Australian-Chinese research team has created the world's thinnest hologram, paving the way towards the integration of 3D holography into everyday...
In the race to produce a quantum computer, a number of projects are seeking a way to create quantum bits -- or qubits -- that are stable, meaning they are not much affected by changes in their environment. This normally needs highly nonlinear non-dissipative elements capable of functioning at very low temperatures.
In pursuit of this goal, researchers at EPFL's Laboratory of Photonics and Quantum Measurements LPQM (STI/SB), have investigated a nonlinear graphene-based...
Dental plaque and the viscous brown slime in drainpipes are two familiar examples of bacterial biofilms. Removing such bacterial depositions from surfaces is...
23.05.2017 | Event News
22.05.2017 | Event News
17.05.2017 | Event News
23.05.2017 | Physics and Astronomy
23.05.2017 | Life Sciences
23.05.2017 | Medical Engineering