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Chatri, Kirtika

Pharmacology

2021

M.S.

Cryptosporidium is an apicomplexan parasite responsible for waterborne outbreaks of diarrheal disease worldwide. There are two species of Cryptosporidium that are important enteric pathogens for humans. The disease, Cryptosporidiosis, is a major cause of childhood diarrhea and an important factor in childhood malnutrition and also a high rate of death (Sparks et al., 2015). It is also more frequent and severe in malnourished children under 3 years of age and immune-compromised individuals, such as AIDS and transplant patients. A common treatment which has greatly reduced diarrhea-associated mortality is oral rehydration therapy; however, enteric infections still persist (Guerrant, DeBoer, Moore, Scharf, & Lima, 2013). This infection disrupts intestinal absorptive and barrier functions, resulting in up to 43% of stunted growth, affecting one-fifth of children worldwide and one-third of children in developing countries. Nitazoxanide is the only proven anti-parasitic treatment for Cryptosporidium infections, but it is not effective in immune-compromised patients. There have also not been enough studies for this drug on infants. This limitation of treatment options presents a major public health challenge given the important burden of disease.The repurposing of drugs developed for other indications and the development of inhibitors for novel targets offers hope of improved therapies for otherwise neglected tropical diseases. In line with this strategy, many of the anticryptosporidial drug leads in development were identified by screening compounds with known antimicrobial activity. The piperazine-based compound MMV665917 is particularly promising anti cryptosporidium lead that was originally identified by screening the Medicines for Malaria Venture (MMV) Malaria Box, a small library of compounds with antimalarial activity (R. S. Jumani et., 2018). My research is intended to address several limitations of MMV665917, which is being optimized in collaboration with a medicinal chemistry group. Using traditional SAR studies, we will improve the potency of MMV665917 while eliminating the side effects associated with inhibition of CYP3A4 and the hERG, gene (KCNH2), an alpha subunit of a potassium ion channel responsible for repolarization of cardiac myocytes.Inhibition of hERG isassociatedwithcardiacarrhythmias.