TiPs: A database of therapeutic targets in pathogens and associated tools

Motivation: The need for new drugs and new targets is particularly compelling in an era that is witnessing an alarming increase of drug resistance in human pathogens. The identification of new targets of known drugs is a promising approach, which has proven successful in several cases. Here, we describe a database that includes information on 5153 putative drug-target pairs for 150 human pathogens derived from available drug-target crystallographic complexes. © 2013 The Author 2013. Published by Oxford University Press. All rights reserved.The need for new drugs and new targets is particularly compelling in an era that is witnessing an alarming increase of drug resistance in human pathogens. The identification of new targets of known drugs is a promising approach, which has proven successful in several cases. Here, we describe a database that includes information on 5153 putative drug-target pairs for 150 human pathogens derived from available drug-target crystallographic complexes

Artemether resistance in vitro is linked to mutations in PfATP6 that also interact with mutations in PfMDR1 in travellers returning with Plasmodium falciparum infections.

BACKGROUND: Monitoring resistance phenotypes for Plasmodium falciparum, using in vitro growth assays, and relating findings to parasite genotype has proved particularly challenging for the study of resistance to artemisinins. METHODS: Plasmodium falciparum isolates cultured from 28 returning travellers diagnosed with malaria were assessed for sensitivity to artemisinin, artemether, dihydroartemisinin and artesunate and findings related to mutations in pfatp6 and pfmdr1. RESULTS: Resistance to artemether in vitro was significantly associated with a pfatp6 haplotype encoding two amino acid substitutions (pfatp6 A623E and S769N; (mean IC50 (95% CI) values of 8.2 (5.7 - 10.7) for A623/S769 versus 623E/769 N 13.5 (9.8 - 17.3) nM with a mean increase of 65%; p = 0.012). Increased copy number of pfmdr1 was not itself associated with increased IC50 values for artemether, but when interactions between the pfatp6 haplotype and increased copy number of pfmdr1 were examined together, a highly significant association was noted with IC50 values for artemether (mean IC50 (95% CI) values of 8.7 (5.9 - 11.6) versus 16.3 (10.7 - 21.8) nM with a mean increase of 87%; p = 0.0068). Previously described SNPs in pfmdr1 are also associated with differences in sensitivity to some artemisinins. CONCLUSIONS: These findings were further explored in molecular modelling experiments that suggest mutations in pfatp6 are unlikely to affect differential binding of artemisinins at their proposed site, whereas there may be differences in such binding associated with mutations in pfmdr1. Implications for a hypothesis that artemisinin resistance may be exacerbated by interactions between PfATP6 and PfMDR1 and for epidemiological studies to monitor emerging resistance are discussed

Identification of the Schistosoma mansoni Molecular Target for the Antimalarial Drug Artemether

Plasmodium falciparum and Schistosoma mansonii are the parasites responsible for most of the malaria and schistosomiasis cases in the world. Notwithstanding their many differences, the two agents have striking similarities in that they both are blood feeders and are targets of an overlapping set of drugs, including the well-known artemether molecule. Here we explore the possibility of using the known information about the mode of action of artemether in Plasmodium to identify the molecular target of the drug in Schistosoma and provide evidence that artemether binds to SmSERCA, a putative Ca(2+)-ATPase of Schistosoma We also predict the putative binding mode of the molecule for both its Plasmodium and Schistosoma targets. Our analysis of the mode of binding of artemether to Ca(2+)-ATPases also provides an explanation for the apparent paradox that, although the molecule has no side effect in humans, it has been shown to possess antitumoral activity

Characterization of amicarbalide derivatives as new antimalarial compounds: Investigation of the mode of action and the mechanism of resistance

Despite the tremendous progress in the fight against malaria during the last two decades, it remains one of the most important infectious diseases worldwide, leading to approximately 500 000 lethal cases annually, mostly among young children. The emergence and spread of resistance of the Plasmodium parasites to all the drugs currently available on the market are a major threat to its control and eradication. It moreover emphasizes the dire need for new antimalarial agents with distinct modes of action. Previously, the medicinal chemistry team at the biotechnology company 4SC AG, Munich, presented a series of promising antimalarial compounds, optimized around an amicarbalide backbone. Two agents were selected out of this series as lead-compounds for further studies, namely SC81458 and SC83288. The work presented here aims to characterize the in vitro activity of the SC-lead compounds. First, it revealed them as potent inhibitors of P. falciparum blood stage parasites, acting preferentially on late stages. The lack of activity on the ring stages is reflected in their fast speed of action, yet not as fast as artemisinin, the fastest compound described so far, that acts on all blood stages. Importantly, the SC-lead compounds were unaffected by the most common resistance mechanisms to antimalarial drugs used in the clinic. Particularly, no cross-resistance mechanism between artemisinin and its derivatives and the SC-lead compounds was observed, and their antiplasmodial modes of action appeared to be distinct from each other. The second part of this work focused on the mode of action of the SC-lead compounds and the mechanisms of resistance that the parasite could develop. Although the Ca2+ ATPase pump PfATP6 was disproved as a direct molecular target of the SC-lead compounds, it was demonstrated to be implicated in a resistance mechanism. The F972Y mutation and the overexpression of the A108T, A109T variant led to a drastic decrease in the SC-lead compounds responsiveness. The F972Y substitution correlated with an in vitro fitness cost for the parasite, which was linked to a lower intracellular calcium resting concentration compared to its parental line. The molecular details of the disturbed calcium homeostasis and its correlation with the resistance to the SC-lead compounds remain to be unraveled. Overall, the findings of this work demonstrate the promising in vitro potency of the SC-lead compounds, particularly SC83288, and highly support its further development into (pre)clinical trials