Genetically Validated Drug Targets in Leishmania: Current Knowledge and Future Prospects

Nathaniel Jones; Carolina Catta Preta; Ana Paula C.A. Lima; Jeremy Charles Mottram

doi:10.1021/acsinfecdis.7b00244

Genetically Validated Drug Targets in Leishmania: Current Knowledge and Future Prospects

Nathaniel Jones, Carolina Catta Preta, Ana Paula C.A. Lima, Jeremy Charles Mottram

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

Abstract

There has been a very limited number of high-throughput screening campaigns carried out with Leishmania drug targets. In part, this is due to the small number of suitable target genes that have been shown by genetic or chemical methods to be essential for the parasite. In this perspective, we discuss the state of genetic target validation in the field of Leishmania research and review the 200 Leishmania genes and 36 Trypanosoma cruzi genes for which gene deletion attempts have been made since the first published case in 1990. We define a quality score for the different genetic deletion techniques that can be used to identify potential drug targets. We also discuss how the advances in genome-scale gene disruption techniques have been used to assist target-based and phenotypic-based drug development in other parasitic protozoa and why Leishmania has lacked a similar approach so far. The prospects for this scale of work are considered in the context of the application of CRISPR/Cas9 gene editing as a useful tool in Leishmania.

Original language	English
Pages (from-to)	467-477
Number of pages	11
Journal	ACS Infectious Diseases
Volume	4
Issue number	4
Early online date	31 Jan 2018
DOIs	https://doi.org/10.1021/acsinfecdis.7b00244
Publication status	Published - 13 Apr 2018

Bibliographical note

Access to Document

10.1021/acsinfecdis.7b00244

Revised manuscript NGJ CCP JCM CLEAN 24-1-17Accepted author manuscript, 1.23 MB
acsinfecdis.7b00244
© 2018 American Chemical Society. Uploaded in accordance with the publisher’s self-archiving policy. Further copying may not be permitted; contact the publisher for details
Final published version, 2.17 MBLicence: CC BY

Cite this

@article{490e36dd80fd44eb964c8a951c8c90e8,

title = "Genetically Validated Drug Targets in Leishmania: Current Knowledge and Future Prospects",

abstract = "There has been a very limited number of high-throughput screening campaigns carried out with Leishmania drug targets. In part, this is due to the small number of suitable target genes that have been shown by genetic or chemical methods to be essential for the parasite. In this perspective, we discuss the state of genetic target validation in the field of Leishmania research and review the 200 Leishmania genes and 36 Trypanosoma cruzi genes for which gene deletion attempts have been made since the first published case in 1990. We define a quality score for the different genetic deletion techniques that can be used to identify potential drug targets. We also discuss how the advances in genome-scale gene disruption techniques have been used to assist target-based and phenotypic-based drug development in other parasitic protozoa and why Leishmania has lacked a similar approach so far. The prospects for this scale of work are considered in the context of the application of CRISPR/Cas9 gene editing as a useful tool in Leishmania.",

author = "Nathaniel Jones and {Catta Preta}, Carolina and Lima, {Ana Paula C.A.} and Mottram, {Jeremy Charles}",

note = "{\textcopyright} 2018 American Chemical Society. Uploaded in accordance with the publisher{\textquoteright}s self-archiving policy. Further copying may not be permitted; contact the publisher for details",

year = "2018",

month = apr,

day = "13",

doi = "10.1021/acsinfecdis.7b00244",

language = "English",

volume = "4",

pages = "467--477",

journal = "ACS Infectious Diseases",

issn = "2373-8227",

publisher = "American Chemical Society",

number = "4",

}

TY - JOUR

T1 - Genetically Validated Drug Targets in Leishmania: Current Knowledge and Future Prospects

AU - Jones, Nathaniel

AU - Catta Preta, Carolina

AU - Lima, Ana Paula C.A.

AU - Mottram, Jeremy Charles

PY - 2018/4/13

Y1 - 2018/4/13

N2 - There has been a very limited number of high-throughput screening campaigns carried out with Leishmania drug targets. In part, this is due to the small number of suitable target genes that have been shown by genetic or chemical methods to be essential for the parasite. In this perspective, we discuss the state of genetic target validation in the field of Leishmania research and review the 200 Leishmania genes and 36 Trypanosoma cruzi genes for which gene deletion attempts have been made since the first published case in 1990. We define a quality score for the different genetic deletion techniques that can be used to identify potential drug targets. We also discuss how the advances in genome-scale gene disruption techniques have been used to assist target-based and phenotypic-based drug development in other parasitic protozoa and why Leishmania has lacked a similar approach so far. The prospects for this scale of work are considered in the context of the application of CRISPR/Cas9 gene editing as a useful tool in Leishmania.

AB - There has been a very limited number of high-throughput screening campaigns carried out with Leishmania drug targets. In part, this is due to the small number of suitable target genes that have been shown by genetic or chemical methods to be essential for the parasite. In this perspective, we discuss the state of genetic target validation in the field of Leishmania research and review the 200 Leishmania genes and 36 Trypanosoma cruzi genes for which gene deletion attempts have been made since the first published case in 1990. We define a quality score for the different genetic deletion techniques that can be used to identify potential drug targets. We also discuss how the advances in genome-scale gene disruption techniques have been used to assist target-based and phenotypic-based drug development in other parasitic protozoa and why Leishmania has lacked a similar approach so far. The prospects for this scale of work are considered in the context of the application of CRISPR/Cas9 gene editing as a useful tool in Leishmania.

U2 - 10.1021/acsinfecdis.7b00244

DO - 10.1021/acsinfecdis.7b00244

M3 - Article

VL - 4

SP - 467

EP - 477

JO - ACS Infectious Diseases

JF - ACS Infectious Diseases

SN - 2373-8227

IS - 4

ER -