Antiparasitic and antibacterial drug discovery: from by Paul M. Selzer

By Paul M. Selzer

Addressing parasitic ailments and people brought on by micro organism, this a lot wanted reference and instruction manual offers a special perception into the method followed via advertisement technology in the direction of infectious illnesses, together with the paintings of medicinal chemists. a number of the authors are scientists with hands-on event of drug discovery devices in the pharmaceutical undefined. furthermore, the textual content covers efforts in the direction of drug improvement in infectious illnesses from educational teams and non revenue businesses

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Glutathione synthetase and γ-glutamylcysteine synthetase are enzymes on the trypanothione synthesis pathway, and MRPA/PGPA exports antimonials and arsenicals as conjugates with trypanothione. Using the same gene array with RNA from methotrexate-resistant cells, increased expressions of the target (dihydrofolate reductase) and pteridine reductase and S-adenosylmethionine synthase were found [98]. Using a different mini-array containing all Leishmania genes encoding ABC proteins, three were found to be overexpressed in antimony-resistant cells [99].

If drug targets are not known, untargeted metabolomics can be used to identify candidate target pathways [167]. Taking samples at different times is important to characterize the drug effect and use of different drug combinations can also be informative. The effects of nifurtimox and DFMO on trypanosomes were studied as a proof of concept [112]. Since DFMO blocks polyamine biosynthesis, and therefore also affects trypanothione production, it was expected to cause oxidative stress. Nifurtimox, meanwhile, was believed to generate oxidative stress.

To our knowledge, there are currently no examples of drugs that directly target these processes in the nucleus or cytosol of protists: the machineries involved may be too similar to those in the mammalian host. However, effects will be seen from inhibitors that prevent the provision of precursors. Structure-Based Prediction In some cases, possible targets can be predicted from chemical structures. For example, huge numbers of inhibitors of mammalian protein kinases are already well characterized and libraries of kinase inhibitors have been published [41].

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