The protozoan parasite Cryptosporidium has caused massive waterborne outbreaks in the U.S, including the 1993 Milwaukee outbreak, where ~400,000 individuals contracted disease, with an economic cost of $31.7 million in medical expenses and another $64.6 million in productivity losses. Highly concentrated Cryptosporidium samples can be prepared with modest effort and simple equipment, and the water supply is easily accessed, leading to its classification as a category B bio-warfare agent. Immunocompromised patients, pregnant women and the elderly are at risk of serious disease; infection can be chronic and fatal in AIDS patients. The tools to respond to such an incident are woefully inadequate: no vaccine or effective drug treatment is currently available. We have discovered that this eukaryotic pathogen has obtained numerous genes by horizontal transfer from bacteria. The enzymes encoded by these bacterial genes provide highly divergent targets for the design of parasite-specific drugs. One such enzyme is IMP dehydrogenase (IMPDH), which catalyzes a key step in guanine nucleotide biosynthesis. Using the RO1 funding mechanism, we have validated IMPDH as a target for parasite treatment and identified ten Principle Hits that selectively inhibit the parasite enzyme. Here we propose a medicinal chemistry program to optimize these compounds and identify a drug candidate with antiparasitic activity in a mouse model of infection: ? Aim 1: Assess principal hits and select four lead compounds for optimization. ? Aim 2: Optimize four Lead Series through a medicinal chemistry program. ? Aim 3: Characterize Advanced Leads in an animal model of Cryptosporidium infection and chose a drug candidate. ? Following selection of the Drug Candidate, and in work not included in this proposal, we will execute a Pre- Clinical Development Plan leading to submission of an IND application to the FDA. ? If successful, the work described in this proposal will develop an urgently needed drug for the management of cryptosporidiosis in epidemic outbreaks and AIDS patients that will be invaluable in the event of a bioterrorist attack. ? ? ?
| Checkley, William; White Jr, A Clinton; Jaganath, Devan et al. (2015) A review of the global burden, novel diagnostics, therapeutics, and vaccine targets for cryptosporidium. Lancet Infect Dis 15:85-94 |
| Sun, Zhuming; Khan, Jihan; Makowska-Grzyska, Magdalena et al. (2014) Synthesis, in vitro evaluation and cocrystal structure of 4-oxo-[1]benzopyrano[4,3-c]pyrazole Cryptosporidium parvum inosine 5'-monophosphate dehydrogenase (CpIMPDH) inhibitors. J Med Chem 57:10544-50 |
| Gorla, Suresh Kumar; McNair, Nina N; Yang, Guangyi et al. (2014) Validation of IMP dehydrogenase inhibitors in a mouse model of cryptosporidiosis. Antimicrob Agents Chemother 58:1603-14 |
| Gorla, Suresh Kumar; Kavitha, Mandapati; Zhang, Minjia et al. (2013) Optimization of benzoxazole-based inhibitors of Cryptosporidium parvum inosine 5'-monophosphate dehydrogenase. J Med Chem 56:4028-43 |
| Johnson, Corey R; Gorla, Suresh Kumar; Kavitha, Mandapati et al. (2013) Phthalazinone inhibitors of inosine-5'-monophosphate dehydrogenase from Cryptosporidium parvum. Bioorg Med Chem Lett 23:1004-7 |
| Kirubakaran, Sivapriya; Gorla, Suresh Kumar; Sharling, Lisa et al. (2012) Structure-activity relationship study of selective benzimidazole-based inhibitors of Cryptosporidium parvum IMPDH. Bioorg Med Chem Lett 22:1985-8 |
| Gorla, Suresh Kumar; Kavitha, Mandapati; Zhang, Minjia et al. (2012) Selective and potent urea inhibitors of cryptosporidium parvum inosine 5'-monophosphate dehydrogenase. J Med Chem 55:7759-71 |
| Long, Marcus J C; Gollapalli, Deviprasad R; Hedstrom, Lizbeth (2012) Inhibitor mediated protein degradation. Chem Biol 19:629-37 |
| MacPherson, Iain S; Temme, J Sebastian; Habeshian, Sevan et al. (2011) Multivalent glycocluster design through directed evolution. Angew Chem Int Ed Engl 50:11238-42 |
| Hedstrom, L; Liechti, G; Goldberg, J B et al. (2011) The antibiotic potential of prokaryotic IMP dehydrogenase inhibitors. Curr Med Chem 18:1909-18 |
Showing the most recent 10 out of 15 publications
