Drug Discovery for Parasitic Diseases
Using African sleeping sickness trypanosomes as a model for Chagas, leishmaniasis, and toxoplasmosis
Dr. Marilyn Parsons conducts research on orphan infectious diseases caused by protozoan parasites. These disease agents are eukaryotic, so unlike bacteria, their cellular features and biochemical processes resemble human cells. These similarities make identifying unique drug targets challenging. The Parsons lab has expertise in analyzing gene expression to identify novel drug targets, including proficiency with ribosome profiling that uses RNAseq to identify proteins as they are translated.
For drug discovery, the lab focuses on protozoan protein kinases that have features that make them essential to the parasite yet distinct from human kinases. Dr. Parsons' research includes validating that the kinases are essential, screening small compound libraries for inhibitors, assaying candidate compounds in vitro in cultured parasites, and testing the inhibitors in vivo in infected mice. In a collaborative effort with others around the world, this approach has yielded promising inhibitors of CDPK1, an essential kinase of Toxoplasma gondii. This protozoan is responsible for toxoplasmosis, which causes encephalitis in people with AIDS and miscarriages and birth defects in animals and humans.
The Parsons lab now primarily works on the African trypanosome that causes the neglected infectious disease human African trypanosomiasis (African sleeping sickness). This disease is found in sub-Saharan Africa, where it is spread by the tsetse fly. It is almost always fatal unless treated (and current treatment regimens are problematic), and there is no vaccine on the horizon.
In addition to finding drugs for trypanosomiasis that are less toxic and less susceptible to resistance than current treatments, Dr. Parsons uses the African trypanosome as a model for protozoan diseases whose causative agents are more difficult to culture and genetically manipulate. Examples are Chagas’ disease (known as kissing bug disease) and leishmaniasis, the visceral form of which is particularly dangerous for children. The Parsons group has extensive experience culturing and altering African trypanosomes, and is using CRISPR/Cas9 gene editing, to facilitate drug discovery.
Stage of Development
- Preclinical in vitro and in vivo
- Collaborative research opportunity
- Sponsored research agreement
- Consultation agreement
- Parasite culturing and genetic engineering
- In vitro and in vivo testing
- Scheele S, Geiger JA, DeRocher AE, Choi R, Smith TR...Parsons M. Toxoplasma calcium-dependent protein kinase 1 inhibitors: probing activity and resistance using cellular thermal shift assays. Antimicrob Agents Chemother. 2018;62:e00051-18.
- Jensen BC, Booster N, Vidadala RSR, Maly DJ, Parsons M. A novel protein kinase is essential in bloodstream Trypanosoma brucei. Int J Parasitol. 2016;46(8):479-483.
- Vidadala RSR, Rivas KL, Ojo KK, Hulverson MA, Zambriski JA...Parsons M, et al. Development of an orally available and central nervous system (CNS) penetrant Toxoplasma gondii calcium-dependent protein kinase 1 (TgCDPK1) inhibitor with minimal human ether-a-go-go-related gene (hERG) activity for the treatment of toxoplasmosis. J Med Chem. 2016;59(13):6531-6546.
- Antwi EB, Haanstra JR, Ramasamy G, Jensen B, Droll D, Rojas F...Parsons M, Clayton C. Integrative analysis of the Trypanosoma brucei gene expression cascade predicts differential regulation of mRNA processing and unusual control of ribosomal protein expression. BMC Genomics. 2016;17:306.
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