A screen against Leishmania intracellular amastigotes: comparison to a promastigote screen and identification of a host cell-specific hit.
The ability to screen compounds in a high-throughput manner is essential in the process of small molecule drug discovery. Critical to the success of screening strategies is the proper design of the assay, often implying a compromise between ease/speed and a biologically relevant setting. Leishmanias...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2011-07-01
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| Series: | PLoS Neglected Tropical Diseases |
| Online Access: | http://europepmc.org/articles/PMC3139667?pdf=render |
| _version_ | 1818129470378213376 |
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| author | Geraldine De Muylder Kenny K H Ang Steven Chen Michelle R Arkin Juan C Engel James H McKerrow |
| author_facet | Geraldine De Muylder Kenny K H Ang Steven Chen Michelle R Arkin Juan C Engel James H McKerrow |
| author_sort | Geraldine De Muylder |
| collection | DOAJ |
| description | The ability to screen compounds in a high-throughput manner is essential in the process of small molecule drug discovery. Critical to the success of screening strategies is the proper design of the assay, often implying a compromise between ease/speed and a biologically relevant setting. Leishmaniasis is a major neglected disease with limited therapeutic options. In order to streamline efforts for the design of productive drug screens against Leishmania, we compared the efficiency of two screening methods, one targeting the free living and easily cultured promastigote (insect-infective) stage, the other targeting the clinically relevant but more difficult to culture intra-macrophage amastigote (mammal-infective) stage. Screening of a 909-member library of bioactive compounds against Leishmania donovani revealed 59 hits in the promastigote primary screen and 27 in the intracellular amastigote screen, with 26 hits shared by both screens. This suggested that screening against the promastigote stage, although more suitable for automation, fails to identify all active compounds and leads to numerous false positive hits. Of particular interest was the identification of one compound specific to the infective amastigote stage of the parasite. This compound affects intracellular but not axenic parasites, suggesting a host cell-dependent mechanism of action, opening new avenues for anti-leishmanial chemotherapy. |
| first_indexed | 2024-12-11T07:49:39Z |
| format | Article |
| id | doaj.art-6613cfa0133b45b99845a0f1b17c6da1 |
| institution | Directory Open Access Journal |
| issn | 1935-2727 1935-2735 |
| language | English |
| last_indexed | 2024-12-11T07:49:39Z |
| publishDate | 2011-07-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Neglected Tropical Diseases |
| spelling | doaj.art-6613cfa0133b45b99845a0f1b17c6da12022-12-22T01:15:22ZengPublic Library of Science (PLoS)PLoS Neglected Tropical Diseases1935-27271935-27352011-07-0157e125310.1371/journal.pntd.0001253A screen against Leishmania intracellular amastigotes: comparison to a promastigote screen and identification of a host cell-specific hit.Geraldine De MuylderKenny K H AngSteven ChenMichelle R ArkinJuan C EngelJames H McKerrowThe ability to screen compounds in a high-throughput manner is essential in the process of small molecule drug discovery. Critical to the success of screening strategies is the proper design of the assay, often implying a compromise between ease/speed and a biologically relevant setting. Leishmaniasis is a major neglected disease with limited therapeutic options. In order to streamline efforts for the design of productive drug screens against Leishmania, we compared the efficiency of two screening methods, one targeting the free living and easily cultured promastigote (insect-infective) stage, the other targeting the clinically relevant but more difficult to culture intra-macrophage amastigote (mammal-infective) stage. Screening of a 909-member library of bioactive compounds against Leishmania donovani revealed 59 hits in the promastigote primary screen and 27 in the intracellular amastigote screen, with 26 hits shared by both screens. This suggested that screening against the promastigote stage, although more suitable for automation, fails to identify all active compounds and leads to numerous false positive hits. Of particular interest was the identification of one compound specific to the infective amastigote stage of the parasite. This compound affects intracellular but not axenic parasites, suggesting a host cell-dependent mechanism of action, opening new avenues for anti-leishmanial chemotherapy.http://europepmc.org/articles/PMC3139667?pdf=render |
| spellingShingle | Geraldine De Muylder Kenny K H Ang Steven Chen Michelle R Arkin Juan C Engel James H McKerrow A screen against Leishmania intracellular amastigotes: comparison to a promastigote screen and identification of a host cell-specific hit. PLoS Neglected Tropical Diseases |
| title | A screen against Leishmania intracellular amastigotes: comparison to a promastigote screen and identification of a host cell-specific hit. |
| title_full | A screen against Leishmania intracellular amastigotes: comparison to a promastigote screen and identification of a host cell-specific hit. |
| title_fullStr | A screen against Leishmania intracellular amastigotes: comparison to a promastigote screen and identification of a host cell-specific hit. |
| title_full_unstemmed | A screen against Leishmania intracellular amastigotes: comparison to a promastigote screen and identification of a host cell-specific hit. |
| title_short | A screen against Leishmania intracellular amastigotes: comparison to a promastigote screen and identification of a host cell-specific hit. |
| title_sort | screen against leishmania intracellular amastigotes comparison to a promastigote screen and identification of a host cell specific hit |
| url | http://europepmc.org/articles/PMC3139667?pdf=render |
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