Trypanothione Reductase High-Throughput Screening Campaign Identifies Novel Classes of Inhibitors with Antiparasitic Activity

Georgina A. Holloway; William N. Charman; Alan H. Fairlamb; Reto Brun; Marcel Kaiser; Edmund Kostewicz; Patrizia M. Novello; John P. Parisot; John Richardson; Ian P. Street; Keith G. Watson; Jonathan B. Baell

doi:10.1128/AAC.01568-08

Trypanothione Reductase High-Throughput Screening Campaign Identifies Novel Classes of Inhibitors with Antiparasitic Activity

Georgina A. Holloway
, William N. Charman
, Alan H. Fairlamb
, Reto Brun
, Marcel Kaiser
, Edmund Kostewicz
, Patrizia M. Novello
, John P. Parisot
, John Richardson
, Ian P. Street
, Keith G. Watson
, Jonathan B. Baell

Research output: Contribution to journal › Article › peer-review

70 Citations (Scopus)

Abstract

High-throughput screening of 100,000 lead-like compounds led to the identification of nine novel chemical classes of trypanothione reductase (TR) inhibitors worthy of further investigation. Hits from five of these chemical classes have been developed further through different combinations of preliminary structure-activity relationship rate probing and assessment of antiparasitic activity, cytotoxicity, and chemical and in vitro metabolic properties. This has led to the identification of novel TR inhibitor chemotypes that are drug-like and display antiparasitic activity. For one class, a series of analogues have displayed a correlation between TR inhibition and antiparasitic activity. This paper explores the process of identifying, investigating, and evaluating a series of hits from a high-throughput screening campaign.

Original language	English
Pages (from-to)	2824-2833
Number of pages	10
Journal	Antimicrobial Agents and Chemotherapy
Volume	53
Issue number	7
DOIs	https://doi.org/10.1128/AAC.01568-08
Publication status	Published - Jul 2009

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

TRYPANOSOMA-CRUZI
CRYSTAL-STRUCTURE
DRUG DISCOVERY
CHAGAS-DISEASE
GLUTATHIONE-REDUCTASE
REDOX METABOLISM
OXIDATIVE STRESS
DESIGN
LEISHMANIA
SUBSTRATE

Access to Document

10.1128/AAC.01568-08

Aref#d: 18185. Characterization and validation of drug targets in the Kinetoplastida (Principal Research Fellowship/Programme Grant)
Fairlamb, A. (Investigator)
1/10/06 → 30/09/17
Project: Research

Cite this

Holloway, G. A., Charman, W. N., Fairlamb, A. H., Brun, R., Kaiser, M., Kostewicz, E., Novello, P. M., Parisot, J. P., Richardson, J., Street, I. P., Watson, K. G., & Baell, J. B. (2009). Trypanothione Reductase High-Throughput Screening Campaign Identifies Novel Classes of Inhibitors with Antiparasitic Activity. Antimicrobial Agents and Chemotherapy, 53(7), 2824-2833. https://doi.org/10.1128/AAC.01568-08

@article{3df984b8aa594c348a2b2fc1a89e9b36,

title = "Trypanothione Reductase High-Throughput Screening Campaign Identifies Novel Classes of Inhibitors with Antiparasitic Activity",

abstract = "High-throughput screening of 100,000 lead-like compounds led to the identification of nine novel chemical classes of trypanothione reductase (TR) inhibitors worthy of further investigation. Hits from five of these chemical classes have been developed further through different combinations of preliminary structure-activity relationship rate probing and assessment of antiparasitic activity, cytotoxicity, and chemical and in vitro metabolic properties. This has led to the identification of novel TR inhibitor chemotypes that are drug-like and display antiparasitic activity. For one class, a series of analogues have displayed a correlation between TR inhibition and antiparasitic activity. This paper explores the process of identifying, investigating, and evaluating a series of hits from a high-throughput screening campaign.",

keywords = "TRYPANOSOMA-CRUZI, CRYSTAL-STRUCTURE, DRUG DISCOVERY, CHAGAS-DISEASE, GLUTATHIONE-REDUCTASE, REDOX METABOLISM, OXIDATIVE STRESS, DESIGN, LEISHMANIA, SUBSTRATE",

author = "Holloway, \{Georgina A.\} and Charman, \{William N.\} and Fairlamb, \{Alan H.\} and Reto Brun and Marcel Kaiser and Edmund Kostewicz and Novello, \{Patrizia M.\} and Parisot, \{John P.\} and John Richardson and Street, \{Ian P.\} and Watson, \{Keith G.\} and Baell, \{Jonathan B.\}",

year = "2009",

month = jul,

doi = "10.1128/AAC.01568-08",

language = "English",

volume = "53",

pages = "2824--2833",

journal = "Antimicrobial Agents and Chemotherapy",

issn = "0066-4804",

publisher = "American Society for Microbiology",

number = "7",

}

Holloway, GA, Charman, WN, Fairlamb, AH, Brun, R, Kaiser, M, Kostewicz, E, Novello, PM, Parisot, JP, Richardson, J, Street, IP, Watson, KG & Baell, JB 2009, 'Trypanothione Reductase High-Throughput Screening Campaign Identifies Novel Classes of Inhibitors with Antiparasitic Activity', Antimicrobial Agents and Chemotherapy, vol. 53, no. 7, pp. 2824-2833. https://doi.org/10.1128/AAC.01568-08

TY - JOUR

T1 - Trypanothione Reductase High-Throughput Screening Campaign Identifies Novel Classes of Inhibitors with Antiparasitic Activity

AU - Holloway, Georgina A.

AU - Charman, William N.

AU - Fairlamb, Alan H.

AU - Brun, Reto

AU - Kaiser, Marcel

AU - Kostewicz, Edmund

AU - Novello, Patrizia M.

AU - Parisot, John P.

AU - Richardson, John

AU - Street, Ian P.

AU - Watson, Keith G.

AU - Baell, Jonathan B.

PY - 2009/7

Y1 - 2009/7

N2 - High-throughput screening of 100,000 lead-like compounds led to the identification of nine novel chemical classes of trypanothione reductase (TR) inhibitors worthy of further investigation. Hits from five of these chemical classes have been developed further through different combinations of preliminary structure-activity relationship rate probing and assessment of antiparasitic activity, cytotoxicity, and chemical and in vitro metabolic properties. This has led to the identification of novel TR inhibitor chemotypes that are drug-like and display antiparasitic activity. For one class, a series of analogues have displayed a correlation between TR inhibition and antiparasitic activity. This paper explores the process of identifying, investigating, and evaluating a series of hits from a high-throughput screening campaign.

AB - High-throughput screening of 100,000 lead-like compounds led to the identification of nine novel chemical classes of trypanothione reductase (TR) inhibitors worthy of further investigation. Hits from five of these chemical classes have been developed further through different combinations of preliminary structure-activity relationship rate probing and assessment of antiparasitic activity, cytotoxicity, and chemical and in vitro metabolic properties. This has led to the identification of novel TR inhibitor chemotypes that are drug-like and display antiparasitic activity. For one class, a series of analogues have displayed a correlation between TR inhibition and antiparasitic activity. This paper explores the process of identifying, investigating, and evaluating a series of hits from a high-throughput screening campaign.

KW - TRYPANOSOMA-CRUZI

KW - CRYSTAL-STRUCTURE

KW - DRUG DISCOVERY

KW - CHAGAS-DISEASE

KW - GLUTATHIONE-REDUCTASE

KW - REDOX METABOLISM

KW - OXIDATIVE STRESS

KW - DESIGN

KW - LEISHMANIA

KW - SUBSTRATE

U2 - 10.1128/AAC.01568-08

DO - 10.1128/AAC.01568-08

M3 - Article

C2 - 19364854

SN - 0066-4804

VL - 53

SP - 2824

EP - 2833

JO - Antimicrobial Agents and Chemotherapy

JF - Antimicrobial Agents and Chemotherapy

IS - 7

ER -

Trypanothione Reductase High-Throughput Screening Campaign Identifies Novel Classes of Inhibitors with Antiparasitic Activity

Abstract

UN SDGs

Keywords

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Projects

Aref#d: 18185. Characterization and validation of drug targets in the Kinetoplastida (Principal Research Fellowship/Programme Grant)

Cite this