Browsing by Subject "Drug discovery"

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    Open Access
    CRIMALDDI: platform technologies and novel anti-malarial drug targets
    (BioMed Central Ltd, 2013) Vial, Henri; Taramelli, Donatella; Boulton, Ian; Ward, Steve; Doerig, Christian; Chibale, Kelly
    The Coordination, Rationalization, and Integration of antiMALarial drug Discovery & Development Initiatives (CRIMALDDI) Consortium, funded by the EU Framework Seven Programme, has attempted, through a series of interactive and facilitated workshops, to develop priorities for research to expedite the discovery of new anti-malarials. This paper outlines the recommendations for the development of enabling technologies and the identification of novel targets.Screening systems must be robust, validated, reproducible, and represent human malaria. They also need to be cost-effective. While such systems exist to screen for activity against blood stage Plasmodium falciparum, they are lacking for other Plasmodium spp. and other stages of the parasite's life cycle. Priority needs to be given to developing high-throughput screens that can identify activity against the liver and sexual stages. This in turn requires other enabling technologies to be developed to allow the study of these stages and to allow for the culture of liver cells and the parasite at all stages of its life cycle.As these enabling technologies become available, they will allow novel drug targets to be studied. Currently anti-malarials are mostly targeting the asexual blood stage of the parasite's life cycle. There are many other attractive targets that need to be investigated. The liver stages and the sexual stages will become more important as malaria control moves towards malaria elimination. Sexual development is a process offering multiple targets, even though the mechanisms of differentiation are still not fully understood. However, designing a drug whose effect is not curative but would be used in asymptomatic patients is difficult given current safety thresholds. Compounds active against the liver schizont would have a prophylactic effect and Plasmodium vivax elimination requires effectors against the dormant liver hypnozoites. It may be that drugs to be used in elimination campaigns will also need to have utility in the control phase. Compounds with activity against blood stages need to be screened for activity against other stages.Natural products should also be a valuable source of new compounds. They often occupy non-Lipinski chemical space and so may reveal valuable new chemotypes.
  • Thumbnail Image
    Item
    Open Access
    Identification of new drug targets and resistance mechanisms in Mycobacterium tuberculosis
    (Public Library of Science, 2013) Ioerger, Thomas R; O'Malley, Theresa; Liao, Reiling; Guinn, Kristine M; Hickey, Mark J; Mohaideen, Nilofar; Murphy, Kenan C; Boshoff, Helena I M; Mizrahi, Valerie; Rubin, Eric J
    Identification of new drug targets is vital for the advancement of drug discovery against Mycobacterium tuberculosis , especially given the increase of resistance worldwide to first- and second-line drugs. Because traditional target-based screening has largely proven unsuccessful for antibiotic discovery, we have developed a scalable platform for target identification in M. tuberculosis that is based on whole-cell screening, coupled with whole-genome sequencing of resistant mutants and recombineering to confirm. The method yields targets paired with whole-cell active compounds, which can serve as novel scaffolds for drug development, molecular tools for validation, and/or as ligands for co-crystallization. It may also reveal other information about mechanisms of action, such as activation or efflux. Using this method, we identified resistance-linked genes for eight compounds with anti-tubercular activity. Four of the genes have previously been shown to be essential: AspS, aspartyl-tRNA synthetase, Pks13, a polyketide synthase involved in mycolic acid biosynthesis, MmpL3, a membrane transporter, and EccB3, a component of the ESX-3 type VII secretion system. AspS and Pks13 represent novel targets in protein translation and cell-wall biosynthesis. Both MmpL3 and EccB3 are involved in membrane transport. Pks13, AspS, and EccB3 represent novel candidates not targeted by existing TB drugs, and the availability of whole-cell active inhibitors greatly increases their potential for drug discovery.