A major cause of the paucity of new starting points for drug discovery is the lack of interaction between academia and industry. Much of the global resource in biology is present in universities, whereas the focus of medicinal chemistry is still largely within industry. Open source drug discovery, with sharing of information, is clearly a first step towards overcoming this gap. But the interface could especially be bridged through a scale-up of open sharing of physical compounds, which would accelerate the finding of new starting points for drug discovery. The Medicines for Malaria Venture Malaria Box is a collection of over 400 compounds representing families of structures identified in phenotypic screens of pharmaceutical and academic libraries against the Plasmodium falciparum malaria parasite. The set has now been distributed to almost 200 research groups globally in the last two years, with the only stipulation that information from the screens is deposited in the public domain. This paper reports for the first time on 236 screens that have been carried out against the Malaria Box and compares these results with 55 assays that were previously published, in a format that allows a meta-analysis of the combined dataset. The combined biochemical and cellular assays presented here suggest mechanisms of action for 135 (34%) of the compounds active in killing multiple life-cycle stages of the malaria parasite, including asexual blood, liver, gametocyte, gametes and insect ookinete stages. In addition, many compounds demonstrated activity against other pathogens, showing hits in assays with 16 protozoa, 7 helminths, 9 bacterial and mycobacterial species, the dengue fever mosquito vector, and the NCI60 human cancer cell line panel of 60 human tumor cell lines. Toxicological, pharmacokinetic and metabolic properties were collected on all the compounds, assisting in the selection of the most promising candidates for murine proof-of-concept experiments and medicinal chemistry programs. The data for all of these assays are presented and analyzed to show how outstanding leads for many indications can be selected. These results reveal the immense potential for translating the dispersed expertise in biological assays involving human pathogens into drug discovery starting points, by providing open access to new families of molecules, and emphasize how a small additional investment made to help acquire and distribute compounds, and sharing the data, can catalyze drug discovery for dozens of different indications. Another lesson is that when multiple screens from different groups are run on the same library, results can be integrated quickly to select the most valuable starting points for subsequent medicinal chemistry efforts.
BackgroundWorldwide hundreds of millions of schistosomiasis patients rely on treatment with a single drug, praziquantel. Therapeutic limitations and the threat of praziquantel resistance underline the need to discover and develop next generation drugs.MethodologyWe studied the antischistosomal properties of the Medicines for Malaria Venture (MMV) malaria box containing 200 diverse drug-like and 200 probe-like compounds with confirmed in vitro activity against Plasmodium falciparum. Compounds were tested against schistosomula and adult Schistosoma mansoni in vitro. Based on in vitro performance, available pharmacokinetic profiles and toxicity data, selected compounds were investigated in vivo.Principal FindingsPromising antischistosomal activity (IC50: 1.4–9.5 µM) was observed for 34 compounds against schistosomula. Three compounds presented IC50 values between 0.8 and 1.3 µM against adult S. mansoni. Two promising early leads were identified, namely a N,N′-diarylurea and a 2,3-dianilinoquinoxaline. Treatment of S. mansoni infected mice with a single oral 400 mg/kg dose of these drugs resulted in significant worm burden reductions of 52.5% and 40.8%, respectively.Conclusions/SignificanceThe two candidates identified by investigating the MMV malaria box are characterized by good pharmacokinetic profiles, low cytotoxic potential and easy chemistry and therefore offer an excellent starting point for antischistosomal drug discovery and development.
A racemic mixture of R and S enantiomers of praziquantel (PZQ) is currently the treatment of choice for schistosomiasis. Though the S enantiomer and the metabolites are presumed to contribute only a little to the activity of the drug, in-depth sideby-side studies are lacking. The aim of this study was to investigate the in vitro activities of PZQ and its main metabolites, namely, R-and S-cis-and R-and S-trans-4=-hydroxypraziquantel, against adult worms and newly transformed schistosomula (NTS). Additionally, we explored the in vivo activity and hepatic shift (i.e., the migration of the worms to the liver) produced by each PZQ enantiomer in mice. Fifty percent inhibitory concentrations of R-PZQ, S-PZQ, and R-trans-and R-cis-4=-hydroxypraziquantel of 0.02, 5.85, 4.08, and 2.42 g/ml, respectively, for adult S. mansoni were determined in vitro. S-trans-and S-cis-4=-hydroxypraziquantel were not active at 100 g/ml. These results are consistent with microcalorimetry data and studies with NTS. In vivo, single 400-mg/kg oral doses of R-PZQ and S-PZQ achieved worm burden reductions of 100 and 19%, respectively. Moreover, worms treated in vivo with S-PZQ displayed an only transient hepatic shift and returned to the mesenteric veins within 24 h. Our data confirm that R-PZQ is the main effector molecule, while S-PZQ and the metabolites do not play a significant role in the antischistosomal properties of PZQ. S chistosomiasis or bilharzia is caused by blood flukes of the genus Schistosoma and is part of the group of neglected tropical diseases affecting more than 207 million people in tropical areas (1-3).The exclusive treatment to date for schistosomiasis is praziquantel (PZQ), which was discovered in the 1970s by Merck and Bayer. PZQ is administered as a racemic mixture of R and S enantiomers in tablets of 600 mg. The recommended dosage to treat schistosomiasis is 20 mg/kg three times in 1 day, and since PZQ does not act on juvenile worms, follow-up treatment 4 to 6 weeks later is strongly advised (4). In preventive chemotherapy programs, PZQ is administered as a single 40-mg/kg dose to at-risk populations (5). PZQ undergoes significant first-pass metabolism through the liver enzyme cytochrome P450 (CYP) 3A4 and to a lesser extent through 1A2 and 2C19 (6). R-PZQ is metabolized at a much higher rate than S-PZQ. R-PZQ is transformed mainly into cis-and trans-hydroxypraziquantel (4-OH-PZQ), while S-PZQ is converted to other monohydroxylated metabolites. In rat liver microsomes, the main metabolite is cis-4-OH-PZQ (7, 8), while in humans it is trans-4-OH-PZQ (9).The difference in the antischistosomal activity of each PZQ enantiomer has been known since 1983 (10), and several studies have observed greater activity of R-PZQ than of S-PZQ in vitro and in vivo (11)(12)(13). A clinical trial with Schistosoma japonicuminfected patients also recorded a higher efficacy of R-PZQ than of racemic PZQ at the same dosage (14, 15). Additionally, treatment with R-PZQ resulted in fewer adverse events than the standard treatment (14). However, ...
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