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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.
PMID
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Authors

Mayor MeshTerms
Keywords
Journal Title plos neglected tropical diseases
Publication Year Start




PMID- 29287089
OWN - NLM
STAT- Publisher
LR  - 20171229
IS  - 1935-2735 (Electronic)
IS  - 1935-2727 (Linking)
VI  - 11
IP  - 12
DP  - 2017 Dec 29
TI  - Discovery of novel, orally bioavailable, antileishmanial compounds using
      phenotypic screening.
PG  - e0006157
LID - 10.1371/journal.pntd.0006157 [doi]
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 muM. 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.
FAU - Ortiz, Diana
AU  - Ortiz D
AD  - Department of Molecular Microbiology & Immunology, Oregon Health & Science
      University, Portland, Oregon, United States of America.
FAU - Guiguemde, W Armand
AU  - Guiguemde WA
AD  - Department of Chemical Biology and Theraputics, St. Jude Children's Research
      Hospital, Memphis, Tennessee, United States of America.
FAU - Hammill, Jared T
AU  - Hammill JT
AD  - Department of Chemical Biology and Theraputics, St. Jude Children's Research
      Hospital, Memphis, Tennessee, United States of America.
FAU - Carrillo, Angela K
AU  - Carrillo AK
AD  - Department of Chemical Biology and Theraputics, St. Jude Children's Research
      Hospital, Memphis, Tennessee, United States of America.
FAU - Chen, Yizhe
AU  - Chen Y
AD  - Department of Chemical Biology and Theraputics, St. Jude Children's Research
      Hospital, Memphis, Tennessee, United States of America.
FAU - Connelly, Michele
AU  - Connelly M
AD  - Department of Chemical Biology and Theraputics, St. Jude Children's Research
      Hospital, Memphis, Tennessee, United States of America.
FAU - Stalheim, Kayla
AU  - Stalheim K
AD  - Department of Molecular Microbiology & Immunology, Oregon Health & Science
      University, Portland, Oregon, United States of America.
FAU - Elya, Carolyn
AU  - Elya C
AD  - Department of Molecular Microbiology & Immunology, Oregon Health & Science
      University, Portland, Oregon, United States of America.
FAU - Johnson, Alex
AU  - Johnson A
AD  - Department of Molecular Microbiology & Immunology, Oregon Health & Science
      University, Portland, Oregon, United States of America.
FAU - Min, Jaeki
AU  - Min J
AD  - Department of Chemical Biology and Theraputics, St. Jude Children's Research
      Hospital, Memphis, Tennessee, United States of America.
FAU - Shelat, Anang
AU  - Shelat A
AD  - Department of Chemical Biology and Theraputics, St. Jude Children's Research
      Hospital, Memphis, Tennessee, United States of America.
FAU - Smithson, David C
AU  - Smithson DC
AD  - Department of Chemical Biology and Theraputics, St. Jude Children's Research
      Hospital, Memphis, Tennessee, United States of America.
FAU - Yang, Lei
AU  - Yang L
AD  - Department of Chemical Biology and Theraputics, St. Jude Children's Research
      Hospital, Memphis, Tennessee, United States of America.
FAU - Zhu, Fangyi
AU  - Zhu F
AD  - Department of Chemical Biology and Theraputics, St. Jude Children's Research
      Hospital, Memphis, Tennessee, United States of America.
FAU - Guy, R Kiplin
AU  - Guy RK
AD  - Department of Chemical Biology and Theraputics, St. Jude Children's Research
      Hospital, Memphis, Tennessee, United States of America.
FAU - Landfear, Scott M
AU  - Landfear SM
AUID- ORCID: http://orcid.org/0000-0002-1643-6664
AD  - Department of Molecular Microbiology & Immunology, Oregon Health & Science
      University, Portland, Oregon, United States of America.
LA  - eng
PT  - Journal Article
DEP - 20171229
PL  - United States
TA  - PLoS Negl Trop Dis
JT  - PLoS neglected tropical diseases
JID - 101291488
EDAT- 2017/12/30 06:00
MHDA- 2017/12/30 06:00
CRDT- 2017/12/30 06:00
PHST- 2017/09/06 00:00 [received]
PHST- 2017/12/09 00:00 [accepted]
PHST- 2017/12/30 06:00 [entrez]
PHST- 2017/12/30 06:00 [pubmed]
PHST- 2017/12/30 06:00 [medline]
AID - 10.1371/journal.pntd.0006157 [doi]
AID - PNTD-D-17-01423 [pii]
PST - aheadofprint
SO  - PLoS Negl Trop Dis. 2017 Dec 29;11(12):e0006157. doi:
      10.1371/journal.pntd.0006157.