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 Landfear

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

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 medicinal chemistry optimization of these newly identified scaffolds will lead to promising candidates for an orally available anti-parasitic drug.

Original languageEnglish (US)
Pages (from-to)e0006157
JournalPLoS Neglected Tropical Diseases
Volume11
Issue number12
DOIs
StatePublished - Dec 1 2017
Externally publishedYes

Fingerprint

Parasitic Diseases
Leishmaniasis
miltefosine
Parasites
Pharmacokinetics
Macrophages
Drug Therapy
Cutaneous Leishmaniasis
Trypanosomiasis
Pharmaceutical Chemistry
Leishmania
Growth
Life Cycle Stages
Drug Resistance
Nucleic Acids
Libraries
Coloring Agents
Infection
Pharmaceutical Preparations
Therapeutics

ASJC Scopus subject areas

  • Public Health, Environmental and Occupational Health
  • Infectious Diseases

Cite this

Discovery of novel, orally bioavailable, antileishmanial compounds using phenotypic screening. / Ortiz, Diana; Guiguemde, W. Armand; Hammill, Jared T.; Carrillo, Angela K.; Chen, Yizhe; Connelly, Michele; Stalheim, Kayla; Elya, Carolyn; Johnson, Alex; Min, Jaeki; Shelat, Anang; Smithson, David C.; Yang, Lei; Zhu, Fangyi; Guy, R. Kiplin; Landfear, Scott.

In: PLoS Neglected Tropical Diseases, Vol. 11, No. 12, 01.12.2017, p. e0006157.

Research output: Contribution to journalArticle

Ortiz, D, Guiguemde, WA, Hammill, JT, Carrillo, AK, Chen, Y, Connelly, M, Stalheim, K, Elya, C, Johnson, A, Min, J, Shelat, A, Smithson, DC, Yang, L, Zhu, F, Guy, RK & Landfear, S 2017, 'Discovery of novel, orally bioavailable, antileishmanial compounds using phenotypic screening', PLoS Neglected Tropical Diseases, vol. 11, no. 12, pp. e0006157. https://doi.org/10.1371/journal.pntd.0006157
Ortiz, Diana ; Guiguemde, W. Armand ; Hammill, Jared T. ; Carrillo, Angela K. ; Chen, Yizhe ; Connelly, Michele ; Stalheim, Kayla ; Elya, Carolyn ; Johnson, Alex ; Min, Jaeki ; Shelat, Anang ; Smithson, David C. ; Yang, Lei ; Zhu, Fangyi ; Guy, R. Kiplin ; Landfear, Scott. / Discovery of novel, orally bioavailable, antileishmanial compounds using phenotypic screening. In: PLoS Neglected Tropical Diseases. 2017 ; Vol. 11, No. 12. pp. e0006157.
@article{cbab216c190d4b51a969936ef89c2006,
title = "Discovery of novel, orally bioavailable, antileishmanial compounds using phenotypic screening",
abstract = "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 medicinal chemistry optimization of these newly identified scaffolds will lead to promising candidates for an orally available anti-parasitic drug.",
author = "Diana Ortiz and Guiguemde, {W. Armand} and Hammill, {Jared T.} and Carrillo, {Angela K.} and Yizhe Chen and Michele Connelly and Kayla Stalheim and Carolyn Elya and Alex Johnson and Jaeki Min and Anang Shelat and Smithson, {David C.} and Lei Yang and Fangyi Zhu and Guy, {R. Kiplin} and Scott Landfear",
year = "2017",
month = "12",
day = "1",
doi = "10.1371/journal.pntd.0006157",
language = "English (US)",
volume = "11",
pages = "e0006157",
journal = "PLoS Neglected Tropical Diseases",
issn = "1935-2727",
publisher = "Public Library of Science",
number = "12",

}

TY - JOUR

T1 - Discovery of novel, orally bioavailable, antileishmanial compounds using phenotypic screening

AU - Ortiz, Diana

AU - Guiguemde, W. Armand

AU - Hammill, Jared T.

AU - Carrillo, Angela K.

AU - Chen, Yizhe

AU - Connelly, Michele

AU - Stalheim, Kayla

AU - Elya, Carolyn

AU - Johnson, Alex

AU - Min, Jaeki

AU - Shelat, Anang

AU - Smithson, David C.

AU - Yang, Lei

AU - Zhu, Fangyi

AU - Guy, R. Kiplin

AU - Landfear, Scott

PY - 2017/12/1

Y1 - 2017/12/1

N2 - 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 medicinal chemistry optimization of these newly identified scaffolds will lead to promising candidates for an orally available anti-parasitic drug.

AB - 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 medicinal chemistry optimization of these newly identified scaffolds will lead to promising candidates for an orally available anti-parasitic drug.

UR - http://www.scopus.com/inward/record.url?scp=85041861599&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85041861599&partnerID=8YFLogxK

U2 - 10.1371/journal.pntd.0006157

DO - 10.1371/journal.pntd.0006157

M3 - Article

C2 - 29287089

AN - SCOPUS:85041861599

VL - 11

SP - e0006157

JO - PLoS Neglected Tropical Diseases

JF - PLoS Neglected Tropical Diseases

SN - 1935-2727

IS - 12

ER -