Structurally optimized analogs of the retrograde trafficking inhibitor Retro-2cycl limit Leishmania infections.
In infected mammalian cells, Leishmania parasites reside within specialized compartments called parasitophorous vacuoles (LPVs). We have previously shown that Retro-2, a member of a novel class of small retrograde pathway inhibitors caused reduced LPV sizes and lower parasite numbers during experime...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2017-05-01
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| Series: | PLoS Neglected Tropical Diseases |
| Online Access: | http://europepmc.org/articles/PMC5444862?pdf=render |
| _version_ | 1818961035710693376 |
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| author | Evan Craig Charles-Eugene Huyghues-Despointes Chun Yu Emma L Handy Jason K Sello Peter E Kima |
| author_facet | Evan Craig Charles-Eugene Huyghues-Despointes Chun Yu Emma L Handy Jason K Sello Peter E Kima |
| author_sort | Evan Craig |
| collection | DOAJ |
| description | In infected mammalian cells, Leishmania parasites reside within specialized compartments called parasitophorous vacuoles (LPVs). We have previously shown that Retro-2, a member of a novel class of small retrograde pathway inhibitors caused reduced LPV sizes and lower parasite numbers during experimental L. mexicana sp. infections. The purpose of this study was to determine if structural analogs of Retro-2cycl reported to have superior potency in the inhibition of retrograde pathway-dependent phenomena (i.e., polyomavirus cellular infection by polyomavrius and Shiga toxin trafficking in cells) are also more effective than the parent compound at controlling Leishmania infections. In addition to their effects on LPV development, we show that two optimized analogs of Retro-2cycl, DHQZ 36 and DHQZ 36.1 limit Leishmania amazonensis infection in macrophages at EC50 of 13.63+/-2.58μM and10.57+/-2.66μM, respectively, which is significantly lower than 40.15μM the EC50 of Retro-2cycl. In addition, these analogs caused a reversal in Leishmania induced suppression of IL-6 release by infected cells after LPS activation. Moreover, we show that in contrast to Retro-2cycl that is Leishmania static, the analogs can kill Leishmania parasites in axenic cultures, which is a desirable attribute for any drug to treat Leishmania infections. Together, these studies validate and extend the published structure-activity relationship analyses of Retro-2cycl. |
| first_indexed | 2024-12-20T12:07:02Z |
| format | Article |
| id | doaj.art-bf7770f55c804ed49eee5c3ec3267f42 |
| institution | Directory Open Access Journal |
| issn | 1935-2727 1935-2735 |
| language | English |
| last_indexed | 2024-12-20T12:07:02Z |
| publishDate | 2017-05-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Neglected Tropical Diseases |
| spelling | doaj.art-bf7770f55c804ed49eee5c3ec3267f422022-12-21T19:41:22ZengPublic Library of Science (PLoS)PLoS Neglected Tropical Diseases1935-27271935-27352017-05-01115e000555610.1371/journal.pntd.0005556Structurally optimized analogs of the retrograde trafficking inhibitor Retro-2cycl limit Leishmania infections.Evan CraigCharles-Eugene Huyghues-DespointesChun YuEmma L HandyJason K SelloPeter E KimaIn infected mammalian cells, Leishmania parasites reside within specialized compartments called parasitophorous vacuoles (LPVs). We have previously shown that Retro-2, a member of a novel class of small retrograde pathway inhibitors caused reduced LPV sizes and lower parasite numbers during experimental L. mexicana sp. infections. The purpose of this study was to determine if structural analogs of Retro-2cycl reported to have superior potency in the inhibition of retrograde pathway-dependent phenomena (i.e., polyomavirus cellular infection by polyomavrius and Shiga toxin trafficking in cells) are also more effective than the parent compound at controlling Leishmania infections. In addition to their effects on LPV development, we show that two optimized analogs of Retro-2cycl, DHQZ 36 and DHQZ 36.1 limit Leishmania amazonensis infection in macrophages at EC50 of 13.63+/-2.58μM and10.57+/-2.66μM, respectively, which is significantly lower than 40.15μM the EC50 of Retro-2cycl. In addition, these analogs caused a reversal in Leishmania induced suppression of IL-6 release by infected cells after LPS activation. Moreover, we show that in contrast to Retro-2cycl that is Leishmania static, the analogs can kill Leishmania parasites in axenic cultures, which is a desirable attribute for any drug to treat Leishmania infections. Together, these studies validate and extend the published structure-activity relationship analyses of Retro-2cycl.http://europepmc.org/articles/PMC5444862?pdf=render |
| spellingShingle | Evan Craig Charles-Eugene Huyghues-Despointes Chun Yu Emma L Handy Jason K Sello Peter E Kima Structurally optimized analogs of the retrograde trafficking inhibitor Retro-2cycl limit Leishmania infections. PLoS Neglected Tropical Diseases |
| title | Structurally optimized analogs of the retrograde trafficking inhibitor Retro-2cycl limit Leishmania infections. |
| title_full | Structurally optimized analogs of the retrograde trafficking inhibitor Retro-2cycl limit Leishmania infections. |
| title_fullStr | Structurally optimized analogs of the retrograde trafficking inhibitor Retro-2cycl limit Leishmania infections. |
| title_full_unstemmed | Structurally optimized analogs of the retrograde trafficking inhibitor Retro-2cycl limit Leishmania infections. |
| title_short | Structurally optimized analogs of the retrograde trafficking inhibitor Retro-2cycl limit Leishmania infections. |
| title_sort | structurally optimized analogs of the retrograde trafficking inhibitor retro 2cycl limit leishmania infections |
| url | http://europepmc.org/articles/PMC5444862?pdf=render |
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