Trypanosoma cruzi CYP51 inhibitor derived from a Mycobacterium tuberculosis screen hit.
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 14alpha-demethylase (CYP51), a cytochrome P450 enzyme involved in biosynthesis of membrane...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2009-01-01
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| Series: | PLoS Neglected Tropical Diseases |
| Online Access: | http://europepmc.org/articles/PMC2629123?pdf=render |
| _version_ | 1819092590767636480 |
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| author | Chiung-Kuang Chen Patricia S Doyle Liudmila V Yermalitskaya Zachary B Mackey Kenny K H Ang James H McKerrow Larissa M Podust |
| author_facet | Chiung-Kuang Chen Patricia S Doyle Liudmila V Yermalitskaya Zachary B Mackey Kenny K H Ang James H McKerrow Larissa M Podust |
| author_sort | Chiung-Kuang Chen |
| collection | DOAJ |
| description | 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 14alpha-demethylase (CYP51), a cytochrome P450 enzyme involved in biosynthesis of membrane sterols. METHODOLOGY/PRINCIPAL FINDING:In a screening effort targeting Mycobacterium tuberculosis CYP51 (CYP51(Mt)), 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 CYP51(Mt). Subsequent assays against the CYP51 orthologue in T. cruzi, CYP51(Tc), 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:CYP51(Mt)-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 CYP51(Tc). |
| first_indexed | 2024-12-21T22:58:02Z |
| format | Article |
| id | doaj.art-51e432fc4c2944a1abd5e3f1ea664682 |
| institution | Directory Open Access Journal |
| issn | 1935-2727 1935-2735 |
| language | English |
| last_indexed | 2024-12-21T22:58:02Z |
| publishDate | 2009-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Neglected Tropical Diseases |
| spelling | doaj.art-51e432fc4c2944a1abd5e3f1ea6646822022-12-21T18:47:23ZengPublic Library of Science (PLoS)PLoS Neglected Tropical Diseases1935-27271935-27352009-01-0132e37210.1371/journal.pntd.0000372Trypanosoma cruzi CYP51 inhibitor derived from a Mycobacterium tuberculosis screen hit.Chiung-Kuang ChenPatricia S DoyleLiudmila V YermalitskayaZachary B MackeyKenny K H AngJames H McKerrowLarissa M PodustBACKGROUND: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 14alpha-demethylase (CYP51), a cytochrome P450 enzyme involved in biosynthesis of membrane sterols. METHODOLOGY/PRINCIPAL FINDING:In a screening effort targeting Mycobacterium tuberculosis CYP51 (CYP51(Mt)), 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 CYP51(Mt). Subsequent assays against the CYP51 orthologue in T. cruzi, CYP51(Tc), 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:CYP51(Mt)-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 CYP51(Tc).http://europepmc.org/articles/PMC2629123?pdf=render |
| spellingShingle | Chiung-Kuang Chen Patricia S Doyle Liudmila V Yermalitskaya Zachary B Mackey Kenny K H Ang James H McKerrow Larissa M Podust Trypanosoma cruzi CYP51 inhibitor derived from a Mycobacterium tuberculosis screen hit. PLoS Neglected Tropical Diseases |
| title | Trypanosoma cruzi CYP51 inhibitor derived from a Mycobacterium tuberculosis screen hit. |
| title_full | Trypanosoma cruzi CYP51 inhibitor derived from a Mycobacterium tuberculosis screen hit. |
| title_fullStr | Trypanosoma cruzi CYP51 inhibitor derived from a Mycobacterium tuberculosis screen hit. |
| title_full_unstemmed | Trypanosoma cruzi CYP51 inhibitor derived from a Mycobacterium tuberculosis screen hit. |
| title_short | Trypanosoma cruzi CYP51 inhibitor derived from a Mycobacterium tuberculosis screen hit. |
| title_sort | trypanosoma cruzi cyp51 inhibitor derived from a mycobacterium tuberculosis screen hit |
| url | http://europepmc.org/articles/PMC2629123?pdf=render |
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