The burden of cognitive disorders is likely to increase over the coming years due to both increased longevity and altered risk factor patterns, arising from changes in lifestyle, healthcare and society. Vascular dementia with its underlying heterogeneous pathology, is a challenge for clinicians, and is frequently further aggravated by overlap with other neurodegenerative processes. Current Alzheimer's disease drugs have had limited clinical efficacy in treating vascular dementia and none have been approved by major regulatory authorities specifically for this disease.
We recently demonstrated that 2,3,4,5,6-pentahydroxyxanthone (X5) inhibits the in vitro growth of both chloroquine-sensitive and multidrug-resistant strains of P. falciparum. To study the molecular basis of its antimalarial action, we tested X5 and selected hydroxyxanthone analogs as inhibitors of in vitro heme polymerization in a low ionic strength phosphate solution at mildly acidic pH. We found that addition of 1 Eq. of X5 resulted in complete inhibition of polymerization in this system whereas addition of up to 40 Eqs.
Glutathione-S-transferase (GST) activity has been detected in rodent (Plasmodium berghei, P. yoelii), simian (P. knowlesi) and human (P. falciparum) malarial parasites, and in different intraerythrocytic stages of P. knowlesi (schizont > ring > trophozoite). In chloroquine-resistant strains of rodent and human malarial parasites GST activity significantly increases compared to sensitive strains. Further, the increase in enzyme activity is directly related to drug pressure of resistant P. berghei. Complete inhibition of chloroquine-sensitive and resistant P.
Endoperoxide antimalarials based on the ancient Chinese drug Qinghaosu (artemisinin) are currently our major hope in the fight against drug-resistant malaria. Rational drug design based on artemisinin and its analogues is slow as the mechanism of action of these antimalarials is not clear. Here we report that these drugs, at least in part, exert their effect by interfering with the plasmodial hemoglobin catabolic pathway and inhibition of heme polymerization. In an in vitro experiment we observed inhibition of digestive vacuole proteolytic activity of malarial parasite by artemisinin.
Fourier transform infrared (FTIR) and resonance Raman (RR) spectroscopies have been employed to investigate the reductive cleavage of the O-O bond of the endoperoxide moiety of the antimalarial drug artemisinin and its analog trioxane alcohol by hemin dimer. We have recorded FTIR spectra in the nu(O-O) and nu(as)(Fe-O-Fe) regions of artemisinin and of the hemin dimer that show the cleavage of the endoperoxide and that of the hemin dimer, respectively. We observed similar results in the trioxane alcohol/hemin dimer reaction.
A lack of molecular understanding of the targets and mechanisms of artemisinin action has impeded the improvisation of more efficient antimalarials based on this class of endoperoxide drugs. We have synthesized a heme-artemisinin adduct designated as "hemart" to discover if it mediates the ability of artemisinin to inhibit heme polymerization. Hemart mimics heme in binding to Plasmodium falciparum histidine-rich protein II (PfHRP II) but cannot self-polymerize.
In vitro, the heme cofactor of human iron(II) hemoglobin was efficiently and quickly alkylated at meso positions by the peroxide-based antimalarial drug artemisinin, leading to heme-artemisinin-derived covalent adducts. This reaction occurred in the absence of any added protease or in the presence of an excess of an extra non-heme protein, or even when artemisinin was added to hemolysed human blood.
Journal of the American Society for Mass Spectrometry
In this study, we demonstrate, using electrospray ionization mass spectrometry (ESI-MS) and collision-induced dissociation tandem mass spectrometry (ESI-MS/CID/MS), that stable noncovalent complexes can be formed between Fe(III)-heme and antimalarial agents, i.e., quinine, artemisinin, and the artemisinin derivatives, dihydroartemisinin, alpha- and beta-artemether, and beta-arteether. Differences in the binding behavior of the examined drugs with Fe(III)-heme and the stability of the drug-heme complexes are demonstrated.
Elucidation of the principal targets of the action of the antimalarial drug artemisinin is an ongoing pursuit that is important for understanding the action of this drug and for the development of more potent analogues. We have examined the chemical reaction of Hb with artemisinin. The protein-bound haem in Hb has been found to react with artemisinin much faster than is the case with free haem.
The role of haem iron (II) and oxidative stress in the activation and antimalarial activity of artemisinin is unclear. Thus, we submitted malaria parasite to modified culture conditions: artemisinin activity increased by 20-30% under an oxygen-rich atmosphere (20% O2 instead of "standard" 1% O2), and by 40-50% in the presence of carboxy-haemoglobin, and 2% carbon monoxide, conditions which inhibit haem iron (II) reactivity. In all cases, parasite growth and chloroquine activity were unaffected.