The critical role of mode of action studies in kinetoplastid drug discovery

Alan H. Fairlamb; Susan Wyllie

doi:10.3389/fddsv.2023.1185679

The critical role of mode of action studies in kinetoplastid drug discovery

Alan H. Fairlamb (Lead / Corresponding author), Susan Wyllie (Lead / Corresponding author)

Biological Chemistry and Drug Discovery

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

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Abstract

Understanding the target and mode of action of compounds identified by phenotypic screening can greatly facilitate the process of drug discovery and development. Here, we outline the tools currently available for target identification against the neglected tropical diseases, human African trypanosomiasis, visceral leishmaniasis and Chagas’ disease. We provide examples how these tools can be used to identify and triage undesirable mechanisms, to identify potential toxic liabilities in patients and to manage a balanced portfolio of target-based campaigns. We review the primary targets of drugs that are currently in clinical development that were initially identified via phenotypic screening, and whose modes of action affect protein turnover, RNA trans-splicing or signalling in these protozoan parasites.

Original language	English
Article number	1185679
Number of pages	13
Journal	Frontiers in Drug Discovery
Volume	3
DOIs	https://doi.org/10.3389/fddsv.2023.1185679
Publication status	Published - 10 May 2023

Keywords

whole genome sequencing
chemical proteomics
drug resistance
chemical pulldown
metabolomics
trypanosomiasis
leishmaniasis
target identification

UN SDGs

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

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10.3389/fddsv.2023.1185679Licence: CC BY

Final Published VersionFinal published version, 1.65 MBLicence: CC BY

1 Finished
2 Active

A Platform for Drug Target Deconvolution and Exploitation
Gilbert, I. (Investigator), Horn, D. (Investigator), Pawlowic, M. C. (Investigator), Wyatt, P. (Investigator) & Wyllie, S. (Investigator)
31/12/20 → 30/03/25
Project: Research
Wellcome Centre for Anti-Infectives Research
Cook, S. (Investigator), De Rycker, M. (Investigator), Fairlamb, A. (Investigator), Ferguson, M. (Investigator), Field, M. (Investigator), Gilbert, I. (Investigator), Gray, D. (Investigator), Horn, D. (Investigator), Pawlowic, M. C. (Investigator), Read, K. (Investigator), Wyatt, P. (Investigator) & Wyllie, S. (Investigator)
1/04/17 → 31/03/25
Project: Research
Chemical Biology: Leveraging Phenotypic Hits Against Kinetoplastids (Strategic Grant)
Fairlamb, A. (Investigator), Field, M. (Investigator), Gilbert, I. (Investigator), Gray, D. (Investigator), Horn, D. (Investigator) & Wyatt, P. (Investigator)
1/01/15 → 31/12/20
Project: Research

Cite this

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title = "The critical role of mode of action studies in kinetoplastid drug discovery",

abstract = "Understanding the target and mode of action of compounds identified by phenotypic screening can greatly facilitate the process of drug discovery and development. Here, we outline the tools currently available for target identification against the neglected tropical diseases, human African trypanosomiasis, visceral leishmaniasis and Chagas{\textquoteright} disease. We provide examples how these tools can be used to identify and triage undesirable mechanisms, to identify potential toxic liabilities in patients and to manage a balanced portfolio of target-based campaigns. We review the primary targets of drugs that are currently in clinical development that were initially identified via phenotypic screening, and whose modes of action affect protein turnover, RNA trans-splicing or signalling in these protozoan parasites.",

keywords = "whole genome sequencing, chemical proteomics, drug resistance, chemical pulldown, metabolomics, trypanosomiasis, leishmaniasis, target identification",

author = "Fairlamb, {Alan H.} and Susan Wyllie",

note = "Funding Information: This study was supported by the following funding from the Wellcome Trust: a Centre Award (203134/Z/16/Z), a Strategic Award (105021), and an Innovations Award (218448/Z/19/Z). Copyright: {\textcopyright} 2023 Fairlamb and Wyllie.",

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KW - whole genome sequencing

KW - chemical proteomics

KW - drug resistance

KW - chemical pulldown

KW - metabolomics

KW - trypanosomiasis

KW - leishmaniasis

KW - target identification

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DO - 10.3389/fddsv.2023.1185679

M3 - Article

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The critical role of mode of action studies in kinetoplastid drug discovery

Abstract

Keywords

UN SDGs

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Projects

A Platform for Drug Target Deconvolution and Exploitation

Wellcome Centre for Anti-Infectives Research

Chemical Biology: Leveraging Phenotypic Hits Against Kinetoplastids (Strategic Grant)

Cite this