Glycogen Synthase Kinase-3 as a drug target for Trypanosoma brucei African sleeping sickness is a parasitic disease afflicting up to 500,000 persons in Africa, often with fatal outcomes. New therapeutics are needed for African sleeping sickness, caused by Trypanosoma brucei spp. Glycogen synthase kinase-3 is a critical kinase enzyme found in many eukaryotic organisms. In preliminary data, we have shown that: 1) inhibition of T. brucei GSK-3 expression leads to in vitro cell growth arrest;and 2) inhibitors of GSK-3 lead to growth arrest and cell death of T. brucei and their activity against cells correlates with their activity against GSK-3 enzyme. Though GSK-3 inhibitors kill T. brucei, specific GSK-3 inhibitors do not appear toxic to mammals even with chronic administration. Thus, GSK-3 is an excellent target for developing drugs to treat T. brucei infections. The overall purpose of this application is to better understand T. brucei GSK-3 and use this information to develop lead compounds that target GSK-3 for the treatment of African sleeping sickness.
The Aims of this project include: 1) Further develop small molecule GSK-3 inhibitors as potential drugs for African sleeping sickness (""""""""hit to lead"""""""" development);newly synthesized compounds will be tested for specific activity against T. brucei GSK-3 and cells vs, mammalian kinases and cells to improve potency and specificity;2) Use modeling of the T. brucei GSK-3 structure or solve the T. brucei GSK-3 structure and use structure-based-drug development to direct synthesis of compounds in SA #1 to help improve potency of the compounds;and 3) further validate the target by modifying GSK-3 enzyme in T. brucei parasites to be inhibited by specialized molecules that will only inhibit modified GSK-3 enzyme. Having inhibitors that only inhibit T. brucei GSK-3 is key to understanding the biological and pharmacological effects of GSK-3 inhibition on T. brucei parasites. At the end of this project, we will have critical information about GSK-3 inhibitors for the therapy of African sleeping sickness and will have developed 2 to 3 lead compounds to take forward for optimization as potential therapeutics.
Glycogen Synthase Kinase-3 as a drug target for Trypanosoma brucei this project is to investigate Glycogen Synthase Kinase-3 as a possible drug target for T. brucei and to develop new drugs based on the leads we have found. T. brucei infection, causing African Sleeping Sickness, is of public health significance because it is estimated to cause between 300,000 and 500,000 infections per year in Africa, most of which end fatally. The available drugs for T. brucei infection are very toxic, some of them causing up to 5% mortality from the therapy alone. New drugs for this infection are clearly needed.
|Ojo, Kayode K; Eastman, Richard T; Vidadala, Ramasubbarao et al. (2014) A specific inhibitor of PfCDPK4 blocks malaria transmission: chemical-genetic validation. J Infect Dis 209:275-84|
|Keyloun, Katelyn R; Reid, Molly C; Choi, Ryan et al. (2014) The gatekeeper residue and beyond: homologous calcium-dependent protein kinases as drug development targets for veterinarian Apicomplexa parasites. Parasitology 141:1499-509|
|Crowther, Gregory J; Booker, Michael L; He, Min et al. (2014) Cofactor-independent phosphoglycerate mutase from nematodes has limited druggability, as revealed by two high-throughput screens. PLoS Negl Trop Dis 8:e2628|
|Ojo, Kayode K; Reid, Molly C; Kallur Siddaramaiah, Latha et al. (2014) Neospora caninum calcium-dependent protein kinase 1 is an effective drug target for neosporosis therapy. PLoS One 9:e92929|
|Woodland, Andrew; Grimaldi, Raffaella; Luksch, Torsten et al. (2013) From on-target to off-target activity: identification and optimisation of Trypanosoma brucei GSK3 inhibitors and their characterisation as anti-Trypanosoma brucei drug discovery lead molecules. ChemMedChem 8:1127-37|
|Johnson, Steven M; Murphy, Ryan C; Geiger, Jennifer A et al. (2012) Development of Toxoplasma gondii calcium-dependent protein kinase 1 (TgCDPK1) inhibitors with potent anti-toxoplasma activity. J Med Chem 55:2416-26|
|Larson, Eric T; Ojo, Kayode K; Murphy, Ryan C et al. (2012) Multiple determinants for selective inhibition of apicomplexan calcium-dependent protein kinase CDPK1. J Med Chem 55:2803-10|
|Ojo, Kayode K; Pfander, Claudia; Mueller, Natascha R et al. (2012) Transmission of malaria to mosquitoes blocked by bumped kinase inhibitors. J Clin Invest 122:2301-5|
|Ojo, Kayode K; Arakaki, Tracy L; Napuli, Alberto J et al. (2011) Structure determination of glycogen synthase kinase-3 from Leishmania major and comparative inhibitor structure-activity relationships with Trypanosoma brucei GSK-3. Mol Biochem Parasitol 176:98-108|
|Oduor, Richard O; Ojo, Kayode K; Williams, Gareth P et al. (2011) Trypanosoma brucei glycogen synthase kinase-3, a target for anti-trypanosomal drug development: a public-private partnership to identify novel leads. PLoS Negl Trop Dis 5:e1017|
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