Parasite/Antibiotic Drug Discovery

   IMPDH-targeted drugs for Cryptosporidiosis


SK Gorla, M Kavitha, M Zhang , JEW Chin*, X Liu, B Striepen, M Makowska-Grzyska, Y Kim, A Joachimiak, L Hedstrom and GD Cuny. Optimization of benzoxazole-based inhibitors of Cryptosporidium parvum inosine 5’-monophosphate dehydrogenase. J. Med. Chem. 56, 4028-43 (2013). abstract

SK Gorla, M Kavitha, M Zhang, X Liu, L Sharling, DR Gollapalli, B Striepen, L Hedstrom and GD Cuny.  Selective and potent urea inhibitors of Cryptosporidium parvum inosine 5’-monophosphate dehydrogenase. J. Med. Chem. 55, 7759-71 (2012). abstract

MacPherson, Iain S.; Kirubakaran, Sivapriya; Gorla, Suresh Kumar; Riera, Thomas V.; D'Aquino, J. Alejandro; Zhang, Minjia ; Cuny, Gregory D. and Hedstrom, Lizbeth.  The Structural Basis of Cryptosporidium-Specific IMP Dehydrogenase Inhibitor Selectivity. J. Am. Chem. Soc. 132, 1230-1231 (2010). [abstract]

Sharling, Lisa: Liu, Xiaoping; Gollapalli, Deviprasad R.; Maurya, Sushil; Hedstrom, Lizbeth and Striepen, Boris.  A screening pipeline for antiparasitic agents targeting Cryptosporidium inosine monophosphate dehydrogenase. PLoS Neglected Tropical Diseases, 4, e794 (2010). [abstract]

Umejiego, Nwakaso N.;  Gollapalli, Deviprasad;  Sharling, Lisa; Volftsun, Anna; Lu, Jennifer; Benjamin, Nicole N.; Stroupe, Adam H.;  Riera1, Thomas V.; Striepen,, Boris; Hedstrom, Lizbeth.  Targeting a prokaryotic protein in a eukaryotic pathogen:  identification of lead compounds against Cryptosporidiosis. Chem. Biol. 15, 70-77 (2008). [abstract]

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The protozoan parasite Cryptosporidium is a major cause of the 'vicious cycle of diarrhea and malnutrition' in the developing world, an emerging opportunistic pathogen and potential bio-warfare agent.  Cryptosporidium oocytes are resistant to the usual methods of water treatment and have caused spectacular outbreaks such as the infection of 40% of the inhabitants of Milwaukee in 1993.  The drugs currently approved to treat Cryptosporidium infection are largely ineffective.  Drug discovery is challenging because the parasite cannot be maintained continuously in cell culture.  The sequence of the Cryptsporidium genome revealed that the only route to guanine nucleotides is via IMPDH.  Surprisingly, Cryptsporidium obtained its IMPDH gene from bacteria by lateral gene transfer.  We exploited this unexpected evolutionary divergence of parasite and host enzymes by designing a high throughput screen to target the most diverged portion of the IMPDH active site.  This screen has identified ~60 parasite-selective IMPDH inhibitors.  Our medicinal chemistry program has produced over 70 single-digit nanomolar inhibitors from six structural series.   Our best compounds display over 200-fold selectivity in this system.  We now have compounds that exhibit antiparasitic activity in a mouse model of cryptosporidiosis.  The research team includes Boris Striepen (UGA), Greg Cuny (LDDN, Harvard U.), Jan Mead (Emory U.), Wei Yang (FSU) and Barry Snider (Brandeis U.).

see also “ Targeting prokaryotic enzymes in an eukaryotic parasite” and “IMPDH as a target for antibiotic chemotherapy