Ergosterol biosynthesis and drug development for Chagas disease
This article presents an overview of the currently available drugs nifurtimox (NFX) and benznidazole (BZN) used against Trypanosoma cruzi, the aetiological agent of Chagas disease; herein we discuss their limitations along with potential alternatives with a focus on ergosterol biosynthesis inhibitor...
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| Format: | Article |
| Language: | English |
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Fundação Oswaldo Cruz (FIOCRUZ)
2009-07-01
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| Series: | Memorias do Instituto Oswaldo Cruz |
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| Online Access: | http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0074-02762009000900041 |
| _version_ | 1797721230645657600 |
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| author | Julio A Urbina |
| author_facet | Julio A Urbina |
| author_sort | Julio A Urbina |
| collection | DOAJ |
| description | This article presents an overview of the currently available drugs nifurtimox (NFX) and benznidazole (BZN) used against Trypanosoma cruzi, the aetiological agent of Chagas disease; herein we discuss their limitations along with potential alternatives with a focus on ergosterol biosynthesis inhibitors (EBI). These compounds are currently the most advanced candidates for new anti-T. cruzi agents given that they block de novo production of 24-alkyl-sterols, which are essential for parasite survival and cannot be replaced by a host's own cholesterol. Among these compounds, new triazole derivatives that inhibit the parasite's C14± sterol demethylase are the most promising, as they have been shown to have curative activity in murine models of acute and chronic Chagas disease and are active against NFX and BZN-resistant T. cruzi strains; among this class of compounds, posaconazole (Schering-Plough Research Institute) and ravuconazole (Eisai Company) are poised for clinical trials in Chagas disease patients in the short term. Other T. cruzi-specific EBI, with in vitro and in vivo potency, include squalene synthase, lanosterol synthase and squalene epoxidase-inhibitors as well as compounds with dual mechanisms of action (ergosterol biosynthesis inhibition and free radical generation), but they are less advanced in their development process. The main putative advantages of EBI over currently available therapies include their higher potency and selectivity in both acute and chronic infections, activity against NFX and BZN-resistant T. cruzi strains, and much better tolerability and safety profiles. Limitations may include complexity and cost of manufacture of the new compounds. As for any new drug, such compounds will require extensive clinical testing before being introduced for clinical use, and the complexity of such studies, particularly in chronic patients, will be compounded by the current limitations in the verification of true parasitological cures for T. cruzi infections. |
| first_indexed | 2024-03-12T09:31:36Z |
| format | Article |
| id | doaj.art-e18d65265848489ca755eb545b5d5774 |
| institution | Directory Open Access Journal |
| issn | 0074-0276 1678-8060 |
| language | English |
| last_indexed | 2024-03-12T09:31:36Z |
| publishDate | 2009-07-01 |
| publisher | Fundação Oswaldo Cruz (FIOCRUZ) |
| record_format | Article |
| series | Memorias do Instituto Oswaldo Cruz |
| spelling | doaj.art-e18d65265848489ca755eb545b5d57742023-09-02T13:54:22ZengFundação Oswaldo Cruz (FIOCRUZ)Memorias do Instituto Oswaldo Cruz0074-02761678-80602009-07-0110431131810.1590/S0074-02762009000900041Ergosterol biosynthesis and drug development for Chagas diseaseJulio A UrbinaThis article presents an overview of the currently available drugs nifurtimox (NFX) and benznidazole (BZN) used against Trypanosoma cruzi, the aetiological agent of Chagas disease; herein we discuss their limitations along with potential alternatives with a focus on ergosterol biosynthesis inhibitors (EBI). These compounds are currently the most advanced candidates for new anti-T. cruzi agents given that they block de novo production of 24-alkyl-sterols, which are essential for parasite survival and cannot be replaced by a host's own cholesterol. Among these compounds, new triazole derivatives that inhibit the parasite's C14± sterol demethylase are the most promising, as they have been shown to have curative activity in murine models of acute and chronic Chagas disease and are active against NFX and BZN-resistant T. cruzi strains; among this class of compounds, posaconazole (Schering-Plough Research Institute) and ravuconazole (Eisai Company) are poised for clinical trials in Chagas disease patients in the short term. Other T. cruzi-specific EBI, with in vitro and in vivo potency, include squalene synthase, lanosterol synthase and squalene epoxidase-inhibitors as well as compounds with dual mechanisms of action (ergosterol biosynthesis inhibition and free radical generation), but they are less advanced in their development process. The main putative advantages of EBI over currently available therapies include their higher potency and selectivity in both acute and chronic infections, activity against NFX and BZN-resistant T. cruzi strains, and much better tolerability and safety profiles. Limitations may include complexity and cost of manufacture of the new compounds. As for any new drug, such compounds will require extensive clinical testing before being introduced for clinical use, and the complexity of such studies, particularly in chronic patients, will be compounded by the current limitations in the verification of true parasitological cures for T. cruzi infections.http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0074-02762009000900041chemotherapyTrypanosoma cruzisterol biosynthesissterol C14± demethylasesqualene synthaseoxidosqualene cycliseamiodarone |
| spellingShingle | Julio A Urbina Ergosterol biosynthesis and drug development for Chagas disease Memorias do Instituto Oswaldo Cruz chemotherapy Trypanosoma cruzi sterol biosynthesis sterol C14± demethylase squalene synthase oxidosqualene cyclise amiodarone |
| title | Ergosterol biosynthesis and drug development for Chagas disease |
| title_full | Ergosterol biosynthesis and drug development for Chagas disease |
| title_fullStr | Ergosterol biosynthesis and drug development for Chagas disease |
| title_full_unstemmed | Ergosterol biosynthesis and drug development for Chagas disease |
| title_short | Ergosterol biosynthesis and drug development for Chagas disease |
| title_sort | ergosterol biosynthesis and drug development for chagas disease |
| topic | chemotherapy Trypanosoma cruzi sterol biosynthesis sterol C14± demethylase squalene synthase oxidosqualene cyclise amiodarone |
| url | http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0074-02762009000900041 |
| work_keys_str_mv | AT julioaurbina ergosterolbiosynthesisanddrugdevelopmentforchagasdisease |