Editorial to “Disturbances of cardiac wavelength and repolarization precede torsade de pointes and ventricular fibrillation in langendorff perfused rabbit hearts” by Luc Hondeghem ∗: It is difficult to make predictions, especially about the future∗: Thoughts about forecasting cardiotoxicity of pharmacological interventions

The evolution of drug resistance is a recurrent problem that has plagued efforts to treat and control malaria. Recent emergence of artemisinin resistance in Southeast Asia underscores the need to develop novel antimalarials and identify new targetable pathways in Plasmodium parasites. Transmission-blocking approaches, which typically target gametocytes in the host bloodstream or parasite stages in the mosquito gut, are recognized collectively as a strategy that when used in combination with antimalarials that target erythrocytic stages will not only cure malaria but will also prevent subsequent transmission. We tested four derivatives of (+)-usnic acid, a metabolite isolated from lichens, for transmission-blocking activity against Plasmodium falciparum using the standard membrane feeding assay. For two of the derivatives, BT37 and BT122, we observed a consistent dose-response relationship between concentration in the blood meal and oocyst intensity in the midgut. To explore their mechanism of action, we used the murine model Plasmodium berghei and found that both derivatives prevent ookinete maturation. Using fluorescence microscopy, we demonstrated that in the presence of each compound zygote vitality was severely affected, and those that did survive failed to elongate and mature into ookinetes. The observed phenotypes were similar to those described for mutants of specific kinases (NEK2/NEK4) and of inner membrane complex 1 (IMC1) proteins, which are all vital to the zygote-to-ookinete transition. We discuss the implications of our findings and our high-throughput screening approach to identifying next generation, transmission-blocking antimalarials based on the scaffolds of these (+)-usnic acid derivatives

Chemical probe platforms identify targetable molecules and pathways that are involved in Plasmodium gametocyte-to-ookinete transition in the mosquito

Malaria parasite transmission cycles require an obligatory developmental stage in the Anopheles mosquito vector. In the era of global malaria elimination and eradication, there is emergent emphasis on the development of interventions that break the transmission cycle. While there are several existing antimalarials that have been shown to be effective in blocking the parasite\u2019s jump from humans to mosquitoes, to prevent parasite breakthrough resulting from overlapping resistance mechanisms, new pathways that can be targeted by small molecules (and eventually drugs) need to be identified. We used four natural product compounds, two usnic acid derivatives as well as parthenin and parthenolide as chemical probes to explore and identify drug-susceptible pathways during gametocyte-to-ookinete transition. We measured efficacy by a battery of quantitative, functional approaches including high-content fluorescence image capture, imaging flow cytometry and standard membrane feeding assay (SMFA). Two usnic acid (UA) derivatives, BT-122 and BT-37 were extremely potent in blocking P. falciparum and P. berghei zygote-to-ookinete maturation in vivo and in vitro. We further modified BT-37 with a UV-crosslinking probe and identified its putative targets in zygotes by mass spectrometry. We also observed that parthenin appeared to be more effective in blocking gamete-to-zygote formation than parthenolide; although the latter compound has a more promising pharmacological profile based on Phase I clinical trials. Importantly, we noted that exposure of day 15 stage V gametocytes to parthenin (1 \ub5g/ml) for 24 hours, followed by drug wash out and incubation in parthenin-free culture medium for another 24 hours resulted in the complete blockade of mosquito infection as measured by SMFA. Chemical derivitizations of parthenin are being explored to develop a new crosslinking probe to permit subsequent identification of its candidate target molecules in Plasmodium stage V gametocytes. We envision that these studies will illuminate the potential mechanism of action that results in the inactivation of this important transmission stage

A research agenda for malaria eradication: vaccines.

Contains fulltext : 97591.pdf (publisher's version ) (Open Access)Vaccines could be a crucial component of efforts to eradicate malaria. Current attempts to develop malaria vaccines are primarily focused on Plasmodium falciparum and are directed towards reducing morbidity and mortality. Continued support for these efforts is essential, but if malaria vaccines are to be used as part of a repertoire of tools for elimination or eradication of malaria, they will need to have an impact on malaria transmission. We introduce the concept of "vaccines that interrupt malaria transmission" (VIMT), which includes not only "classical" transmission-blocking vaccines that target the sexual and mosquito stages but also pre-erythrocytic and asexual stage vaccines that have an effect on transmission. VIMT may also include vaccines that target the vector to disrupt parasite development in the mosquito. Importantly, if eradication is to be achieved, malaria vaccine development efforts will need to target other malaria parasite species, especially Plasmodium vivax, where novel therapeutic vaccines against hypnozoites or preventive vaccines with effect against multiple stages could have enormous impact. A target product profile (TPP) for VIMT is proposed and a research agenda to address current knowledge gaps and develop tools necessary for design and development of VIMT is presented