Discovery of novel, orally bioavailable, antileishmanial compounds using phenotypic screening.
Leishmaniasis is a parasitic infection that afflicts approximately 12 million people worldwide. There are several limitations to the approved drug therapies for leishmaniasis, including moderate to severe toxicity, growing drug resistance, and the need for extended dosing. Moreover, miltefosine is c...
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ftdoajarticles:oai:doaj.org/article:fd582fbd68d94e90b34293f3995c292e 2023-05-15T15:12:37+02:00 Discovery of novel, orally bioavailable, antileishmanial compounds using phenotypic screening. Diana Ortiz W Armand Guiguemde Jared T Hammill Angela K Carrillo Yizhe Chen Michele Connelly Kayla Stalheim Carolyn Elya Alex Johnson Jaeki Min Anang Shelat David C Smithson Lei Yang Fangyi Zhu R Kiplin Guy Scott M Landfear 2017-12-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0006157 https://doaj.org/article/fd582fbd68d94e90b34293f3995c292e EN eng Public Library of Science (PLoS) http://europepmc.org/articles/PMC5764437?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0006157 https://doaj.org/article/fd582fbd68d94e90b34293f3995c292e PLoS Neglected Tropical Diseases, Vol 11, Iss 12, p e0006157 (2017) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2017 ftdoajarticles https://doi.org/10.1371/journal.pntd.0006157 2022-12-31T14:52:17Z Leishmaniasis is a parasitic infection that afflicts approximately 12 million people worldwide. There are several limitations to the approved drug therapies for leishmaniasis, including moderate to severe toxicity, growing drug resistance, and the need for extended dosing. Moreover, miltefosine is currently the only orally available drug therapy for this infection. We addressed the pressing need for new therapies by pursuing a two-step phenotypic screen to discover novel, potent, and orally bioavailable antileishmanials. First, we conducted a high-throughput screen (HTS) of roughly 600,000 small molecules for growth inhibition against the promastigote form of the parasite life cycle using the nucleic acid binding dye SYBR Green I. This screen identified approximately 2,700 compounds that inhibited growth by over 65% at a single point concentration of 10 μM. We next used this 2700 compound focused library to identify compounds that were highly potent against the disease-causing intra-macrophage amastigote form and exhibited limited toxicity toward the host macrophages. This two-step screening strategy uncovered nine unique chemical scaffolds within our collection, including two previously described antileishmanials. We further profiled two of the novel compounds for in vitro absorption, distribution, metabolism, excretion, and in vivo pharmacokinetics. Both compounds proved orally bioavailable, affording plasma exposures above the half-maximal effective concentration (EC50) concentration for at least 12 hours. Both compounds were efficacious when administered orally in a murine model of cutaneous leishmaniasis. One of the two compounds exerted potent activity against trypanosomes, which are kinetoplastid parasites related to Leishmania species. Therefore, this compound could help control multiple parasitic diseases. The promising pharmacokinetic profile and significant in vivo efficacy observed from our HTS hits highlight the utility of our two-step phenotypic screening strategy and strongly suggest that ... Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLOS Neglected Tropical Diseases 11 12 e0006157 |
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Directory of Open Access Journals: DOAJ Articles |
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English |
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Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
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Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Diana Ortiz W Armand Guiguemde Jared T Hammill Angela K Carrillo Yizhe Chen Michele Connelly Kayla Stalheim Carolyn Elya Alex Johnson Jaeki Min Anang Shelat David C Smithson Lei Yang Fangyi Zhu R Kiplin Guy Scott M Landfear Discovery of novel, orally bioavailable, antileishmanial compounds using phenotypic screening. |
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Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
Leishmaniasis is a parasitic infection that afflicts approximately 12 million people worldwide. There are several limitations to the approved drug therapies for leishmaniasis, including moderate to severe toxicity, growing drug resistance, and the need for extended dosing. Moreover, miltefosine is currently the only orally available drug therapy for this infection. We addressed the pressing need for new therapies by pursuing a two-step phenotypic screen to discover novel, potent, and orally bioavailable antileishmanials. First, we conducted a high-throughput screen (HTS) of roughly 600,000 small molecules for growth inhibition against the promastigote form of the parasite life cycle using the nucleic acid binding dye SYBR Green I. This screen identified approximately 2,700 compounds that inhibited growth by over 65% at a single point concentration of 10 μM. We next used this 2700 compound focused library to identify compounds that were highly potent against the disease-causing intra-macrophage amastigote form and exhibited limited toxicity toward the host macrophages. This two-step screening strategy uncovered nine unique chemical scaffolds within our collection, including two previously described antileishmanials. We further profiled two of the novel compounds for in vitro absorption, distribution, metabolism, excretion, and in vivo pharmacokinetics. Both compounds proved orally bioavailable, affording plasma exposures above the half-maximal effective concentration (EC50) concentration for at least 12 hours. Both compounds were efficacious when administered orally in a murine model of cutaneous leishmaniasis. One of the two compounds exerted potent activity against trypanosomes, which are kinetoplastid parasites related to Leishmania species. Therefore, this compound could help control multiple parasitic diseases. The promising pharmacokinetic profile and significant in vivo efficacy observed from our HTS hits highlight the utility of our two-step phenotypic screening strategy and strongly suggest that ... |
format |
Article in Journal/Newspaper |
author |
Diana Ortiz W Armand Guiguemde Jared T Hammill Angela K Carrillo Yizhe Chen Michele Connelly Kayla Stalheim Carolyn Elya Alex Johnson Jaeki Min Anang Shelat David C Smithson Lei Yang Fangyi Zhu R Kiplin Guy Scott M Landfear |
author_facet |
Diana Ortiz W Armand Guiguemde Jared T Hammill Angela K Carrillo Yizhe Chen Michele Connelly Kayla Stalheim Carolyn Elya Alex Johnson Jaeki Min Anang Shelat David C Smithson Lei Yang Fangyi Zhu R Kiplin Guy Scott M Landfear |
author_sort |
Diana Ortiz |
title |
Discovery of novel, orally bioavailable, antileishmanial compounds using phenotypic screening. |
title_short |
Discovery of novel, orally bioavailable, antileishmanial compounds using phenotypic screening. |
title_full |
Discovery of novel, orally bioavailable, antileishmanial compounds using phenotypic screening. |
title_fullStr |
Discovery of novel, orally bioavailable, antileishmanial compounds using phenotypic screening. |
title_full_unstemmed |
Discovery of novel, orally bioavailable, antileishmanial compounds using phenotypic screening. |
title_sort |
discovery of novel, orally bioavailable, antileishmanial compounds using phenotypic screening. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2017 |
url |
https://doi.org/10.1371/journal.pntd.0006157 https://doaj.org/article/fd582fbd68d94e90b34293f3995c292e |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 11, Iss 12, p e0006157 (2017) |
op_relation |
http://europepmc.org/articles/PMC5764437?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0006157 https://doaj.org/article/fd582fbd68d94e90b34293f3995c292e |
op_doi |
https://doi.org/10.1371/journal.pntd.0006157 |
container_title |
PLOS Neglected Tropical Diseases |
container_volume |
11 |
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12 |
container_start_page |
e0006157 |
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1766343270035619840 |