Fragment-based screening in tandem with phenotypic screening provides novel antiparasitic hits

Antoni R Blaazer, Kristina M Orrling, Anitha Shanmugham, Chimed Jansen, Louis Maes, Ewald Edink, Geert Jan Sterk, Marco Siderius, Paul England, David Bailey, Iwan J P de Esch, Rob Leurs

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

Methods to discover biologically active small molecules include target-based and phenotypic screening approaches. One of the main difficulties in drug discovery is elucidating and exploiting the relationship between drug activity at the protein target and disease modification, a phenotypic endpoint. Fragment-based drug discovery is a target-based approach that typically involves the screening of a relatively small number of fragment-like (molecular weight <300) molecules that efficiently cover chemical space. Here, we report a fragment screening on TbrPDEB1, an essential cyclic nucleotide phosphodiesterase (PDE) from Trypanosoma brucei, and human PDE4D, an off-target, in a workflow in which fragment hits and a series of close analogs are subsequently screened for antiparasitic activity in a phenotypic panel. The phenotypic panel contained T. brucei, Trypanosoma cruzi, Leishmania infantum, and Plasmodium falciparum, the causative agents of human African trypanosomiasis (sleeping sickness), Chagas disease, leishmaniasis, and malaria, respectively, as well as MRC-5 human lung cells. This hybrid screening workflow has resulted in the discovery of various benzhydryl ethers with antiprotozoal activity and low toxicity, representing interesting starting points for further antiparasitic optimization.

LanguageEnglish
Pages131-140
Number of pages10
JournalJournal of Biomolecular Screening
Volume20
Issue number1
DOIs
Publication statusPublished - Jan 2015

Fingerprint

Antiparasitic Agents
African Trypanosomiasis
Screening
Trypanosoma brucei brucei
Workflow
Drug Discovery
Leishmania infantum
Leishmaniasis
Ethers
Chagas Disease
Trypanosoma cruzi
Cyclic Nucleotides
Phosphoric Diester Hydrolases
Plasmodium falciparum
Malaria
Molecules
Molecular Weight
Toxicity
Lung
Molecular weight

Keywords

  • 3',5'-Cyclic-AMP Phosphodiesterases
  • Antiparasitic Agents
  • Chagas Disease
  • Cyclic Nucleotide Phosphodiesterases, Type 4
  • Drug Discovery
  • Drug Evaluation, Preclinical
  • Enzyme Inhibitors
  • Humans
  • Inhibitory Concentration 50
  • Neglected Diseases
  • Parasitic Sensitivity Tests
  • Protozoan Proteins
  • Trypanosoma cruzi
  • Journal Article
  • Research Support, Non-U.S. Gov't

Cite this

Blaazer, Antoni R ; Orrling, Kristina M ; Shanmugham, Anitha ; Jansen, Chimed ; Maes, Louis ; Edink, Ewald ; Sterk, Geert Jan ; Siderius, Marco ; England, Paul ; Bailey, David ; de Esch, Iwan J P ; Leurs, Rob. / Fragment-based screening in tandem with phenotypic screening provides novel antiparasitic hits. In: Journal of Biomolecular Screening. 2015 ; Vol. 20, No. 1. pp. 131-140.
@article{aec5c47ace00400195dbd41ab7ff01af,
title = "Fragment-based screening in tandem with phenotypic screening provides novel antiparasitic hits",
abstract = "Methods to discover biologically active small molecules include target-based and phenotypic screening approaches. One of the main difficulties in drug discovery is elucidating and exploiting the relationship between drug activity at the protein target and disease modification, a phenotypic endpoint. Fragment-based drug discovery is a target-based approach that typically involves the screening of a relatively small number of fragment-like (molecular weight <300) molecules that efficiently cover chemical space. Here, we report a fragment screening on TbrPDEB1, an essential cyclic nucleotide phosphodiesterase (PDE) from Trypanosoma brucei, and human PDE4D, an off-target, in a workflow in which fragment hits and a series of close analogs are subsequently screened for antiparasitic activity in a phenotypic panel. The phenotypic panel contained T. brucei, Trypanosoma cruzi, Leishmania infantum, and Plasmodium falciparum, the causative agents of human African trypanosomiasis (sleeping sickness), Chagas disease, leishmaniasis, and malaria, respectively, as well as MRC-5 human lung cells. This hybrid screening workflow has resulted in the discovery of various benzhydryl ethers with antiprotozoal activity and low toxicity, representing interesting starting points for further antiparasitic optimization.",
keywords = "3',5'-Cyclic-AMP Phosphodiesterases, Antiparasitic Agents, Chagas Disease, Cyclic Nucleotide Phosphodiesterases, Type 4, Drug Discovery, Drug Evaluation, Preclinical, Enzyme Inhibitors, Humans, Inhibitory Concentration 50, Neglected Diseases, Parasitic Sensitivity Tests, Protozoan Proteins, Trypanosoma cruzi, Journal Article, Research Support, Non-U.S. Gov't",
author = "Blaazer, {Antoni R} and Orrling, {Kristina M} and Anitha Shanmugham and Chimed Jansen and Louis Maes and Ewald Edink and Sterk, {Geert Jan} and Marco Siderius and Paul England and David Bailey and {de Esch}, {Iwan J P} and Rob Leurs",
note = "{\circledC} 2014 Society for Laboratory Automation and Screening.",
year = "2015",
month = "1",
doi = "10.1177/1087057114549735",
language = "English",
volume = "20",
pages = "131--140",
journal = "Journal of Biomolecular Screening",
issn = "1087-0571",
publisher = "SAGE Publications Inc.",
number = "1",

}

Blaazer, AR, Orrling, KM, Shanmugham, A, Jansen, C, Maes, L, Edink, E, Sterk, GJ, Siderius, M, England, P, Bailey, D, de Esch, IJP & Leurs, R 2015, 'Fragment-based screening in tandem with phenotypic screening provides novel antiparasitic hits', Journal of Biomolecular Screening, vol. 20, no. 1, pp. 131-140. https://doi.org/10.1177/1087057114549735

Fragment-based screening in tandem with phenotypic screening provides novel antiparasitic hits. / Blaazer, Antoni R; Orrling, Kristina M; Shanmugham, Anitha; Jansen, Chimed; Maes, Louis; Edink, Ewald; Sterk, Geert Jan; Siderius, Marco; England, Paul; Bailey, David; de Esch, Iwan J P; Leurs, Rob.

In: Journal of Biomolecular Screening, Vol. 20, No. 1, 01.2015, p. 131-140.

Research output: Contribution to JournalArticleAcademicpeer-review

TY - JOUR

T1 - Fragment-based screening in tandem with phenotypic screening provides novel antiparasitic hits

AU - Blaazer, Antoni R

AU - Orrling, Kristina M

AU - Shanmugham, Anitha

AU - Jansen, Chimed

AU - Maes, Louis

AU - Edink, Ewald

AU - Sterk, Geert Jan

AU - Siderius, Marco

AU - England, Paul

AU - Bailey, David

AU - de Esch, Iwan J P

AU - Leurs, Rob

N1 - © 2014 Society for Laboratory Automation and Screening.

PY - 2015/1

Y1 - 2015/1

N2 - Methods to discover biologically active small molecules include target-based and phenotypic screening approaches. One of the main difficulties in drug discovery is elucidating and exploiting the relationship between drug activity at the protein target and disease modification, a phenotypic endpoint. Fragment-based drug discovery is a target-based approach that typically involves the screening of a relatively small number of fragment-like (molecular weight <300) molecules that efficiently cover chemical space. Here, we report a fragment screening on TbrPDEB1, an essential cyclic nucleotide phosphodiesterase (PDE) from Trypanosoma brucei, and human PDE4D, an off-target, in a workflow in which fragment hits and a series of close analogs are subsequently screened for antiparasitic activity in a phenotypic panel. The phenotypic panel contained T. brucei, Trypanosoma cruzi, Leishmania infantum, and Plasmodium falciparum, the causative agents of human African trypanosomiasis (sleeping sickness), Chagas disease, leishmaniasis, and malaria, respectively, as well as MRC-5 human lung cells. This hybrid screening workflow has resulted in the discovery of various benzhydryl ethers with antiprotozoal activity and low toxicity, representing interesting starting points for further antiparasitic optimization.

AB - Methods to discover biologically active small molecules include target-based and phenotypic screening approaches. One of the main difficulties in drug discovery is elucidating and exploiting the relationship between drug activity at the protein target and disease modification, a phenotypic endpoint. Fragment-based drug discovery is a target-based approach that typically involves the screening of a relatively small number of fragment-like (molecular weight <300) molecules that efficiently cover chemical space. Here, we report a fragment screening on TbrPDEB1, an essential cyclic nucleotide phosphodiesterase (PDE) from Trypanosoma brucei, and human PDE4D, an off-target, in a workflow in which fragment hits and a series of close analogs are subsequently screened for antiparasitic activity in a phenotypic panel. The phenotypic panel contained T. brucei, Trypanosoma cruzi, Leishmania infantum, and Plasmodium falciparum, the causative agents of human African trypanosomiasis (sleeping sickness), Chagas disease, leishmaniasis, and malaria, respectively, as well as MRC-5 human lung cells. This hybrid screening workflow has resulted in the discovery of various benzhydryl ethers with antiprotozoal activity and low toxicity, representing interesting starting points for further antiparasitic optimization.

KW - 3',5'-Cyclic-AMP Phosphodiesterases

KW - Antiparasitic Agents

KW - Chagas Disease

KW - Cyclic Nucleotide Phosphodiesterases, Type 4

KW - Drug Discovery

KW - Drug Evaluation, Preclinical

KW - Enzyme Inhibitors

KW - Humans

KW - Inhibitory Concentration 50

KW - Neglected Diseases

KW - Parasitic Sensitivity Tests

KW - Protozoan Proteins

KW - Trypanosoma cruzi

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1177/1087057114549735

DO - 10.1177/1087057114549735

M3 - Article

VL - 20

SP - 131

EP - 140

JO - Journal of Biomolecular Screening

T2 - Journal of Biomolecular Screening

JF - Journal of Biomolecular Screening

SN - 1087-0571

IS - 1

ER -