Cryptosporidium parvum (Cp) is a major cause of diarrhea and malnutrition in the developing world.  This protozoan parasite is also a frequent cause of waterborne disease in the developed world and presents a credible bioterrorism threat to potable water supplies.  Although cryptosporidiosis is self-limiting in immune competent adults, it can be fatal in children and immune compromised adults.  Current treatments are restricted to one FDA approved drug (e.g. nitazoxanide) that is not particularly effective.  Therefore, new treatment options are urgently needed.Inosine 5'-monophosphate dehydrogenase (IMPDH) is a metabolic enzyme that catalyzes the NAD+-dependent oxidation of inosine 5'-monophosphate (IMP) to xanthosine monophosphate (XMP).  Since CpIMPDH is structurally distinct from its human counterpart and the organism is completely dependent on this enzyme for the production of guanine nucleotides, we have hypothesized that CpIMPDH may represent a viable molecular target for the development of effective cryptosporidiosis chemotherapy with minimal host toxicity.In this presentation, the structure-activity relationship (SAR) of several structurally distinct compound series of CpIMPDH inhibitors will be highlighted, including descriptions of co-crystallization studies of inhibitors with CpIMPDH and the generation of a pharmacophore model.  In addition, mouse pharmacokinetic and pharmacodynamic studies of CpIMPDH inhibitors will be presented.  These studies will also feature the importance of tissue distribution required for efficacy.  Finally, important questions concerning optimum physical-chemical properties and the impact of CpIMPDH inhibitors on the host's gastrointestinal microbiota will also be discussed.

<i>Cryptosporidium parvum</i> IMPDH inhibitors for the treatment of cryptosporidiosis: SAR, pharmacokinetic and pharmacodynamic studies

247th National Meeting (2014)

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Cryptosporidium parvum IMPDH inhibitors for the treatment of cryptosporidiosis: SAR, pharmacokinetic and pharmacodynamic studies