Browsing by Author "Ang, Kenny K. H."

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    Mining a Cathepsin Inhibitor Library for New Antiparasitic Drug Leads
    Ang, Kenny K. H.; Ratnam, Joseline; Gut, Jiri; Legac, Jennifer; Hansell, Elizabeth; Mackey, Zachary B.; Skrzypczynska, Katarzyna M.; Debnath, Anjan; Engel, Juan C.; Rosenthal, Philip J.; McKerrow, James H.; Arkin, Michelle R.; Renslo, Adam R. (PLOS, 2011-05-01)
    The targeting of parasite cysteine proteases with small molecules is emerging as a possible approach to treat tropical parasitic diseases such as sleeping sickness, Chagas’ disease, and malaria. The homology of parasite cysteine proteases to the human cathepsins suggests that inhibitors originally developed for the latter may be a source of promising lead compounds for the former. We describe here the screening of a unique ,2,100-member cathepsin inhibitor library against five parasite cysteine proteases thought to be relevant in tropical parasitic diseases. Compounds active against parasite enzymes were subsequently screened against cultured Plasmodium falciparum, Trypanosoma brucei brucei and/or Trypanosoma cruzi parasites and evaluated for cytotoxicity to mammalian cells. The end products of this effort include the identification of sub-micromolar cell-active leads as well as the elucidation of structure-activity trends that can guide further optimization efforts.
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    Trypanosoma cruzi CYP51 Inhibitor Derived from a Mycobacterium tuberculosis Screen Hit
    Chen, Chiung-Kuang; Doyle, Patricia S.; Yermalitskaya, Ludmila V.; Mackey, Zachary B.; Ang, Kenny K. H.; McKerrow, James H.; Podust, L.arissa M. (PLOS, 2009-02-01)
    Background: The two front-line drugs for chronic Trypanosoma cruzi infections are limited by adverse side-effects and declining efficacy. One potential new target for Chagas’ disease chemotherapy is sterol 14a-demethylase (CYP51), a cytochrome P450 enzyme involved in biosynthesis of membrane sterols. Methodology/Principal Finding: In a screening effort targeting Mycobacterium tuberculosis CYP51 (CYP51Mt), we previously identified the N-[4-pyridyl]-formamide moiety as a building block capable of delivering a variety of chemotypes into the CYP51 active site. In that work, the binding modes of several second generation compounds carrying this scaffold were determined by high-resolution co-crystal structures with CYP51Mt. Subsequent assays against the CYP51 orthologue in T. cruzi, CYP51Tc, demonstrated that two of the compounds tested in the earlier effort bound tightly to this enzyme. Both were tested in vitro for inhibitory effects against T. cruzi and the related protozoan parasite Trypanosoma brucei, the causative agent of African sleeping sickness. One of the compounds had potent, selective anti–T. cruzi activity in infected mouse macrophages. Cure of treated host cells was confirmed by prolonged incubation in the absence of the inhibiting compound. Discrimination between T. cruzi and T. brucei CYP51 by the inhibitor was largely based on the variability (phenylalanine versus isoleucine) of a single residue at a critical position in the active site. Conclusions/Significance: CYP51Mt-based crystal structure analysis revealed that the functional groups of the two tightly bound compounds are likely to occupy different spaces in the CYP51 active site, suggesting the possibility of combining the beneficial features of both inhibitors in a third generation of compounds to achieve more potent and selective inhibition of CYP51Tc.