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Proc Natl Acad Sci U S A. 2019 Apr 2;116(14):7015-7020. doi: 10.1073/pnas.1814685116. Epub 2019 Mar 20.

Lysyl-tRNA synthetase as a drug target in malaria and cryptosporidiosis.

Author information

1
Wellcome Centre for Anti-Infectives Research, Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, University of Dundee, DD1 5EH Dundee, United Kingdom.
2
Seattle Structural Genomics Center for Infectious Disease, Seattle, WA 98109.
3
Division of Allergy and Infectious Diseases, University of Washington, Seattle, WA 98109.
4
Center for Emerging and Re-emerging Infectious Diseases, University of Washington, Seattle, WA 98109.
5
Beryllium Discovery Corp., Bainbridge Island, WA 98110.
6
Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, GA 30602.
7
Department of Life Sciences, Imperial College, South Kensington, SW7 2AZ London, United Kingdom.
8
Medicines for Malaria Venture, 1215 Geneva 15, Switzerland.
9
The Art of Discovery, 48160 Derio, Bizkaia, Basque Country, Spain.
10
Department of Medicine, University of Vermont, Burlington, VT 05405.
11
Biology Department, Calibr at Scripps Research, La Jolla, CA 92037.
12
Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, CH-4002 Basel, Switzerland.
13
Universität Basel, CH-4003 Basel, Switzerland.
14
Diseases of the Developing World, Global Health, GlaxoSmithKline, 28760 Tres Cantos, Madrid, Spain.
15
Structural Parasitology Group, International Centre for Genetic Engineering and Biotechnology, 110067 New Delhi, India.
16
Malaria Molecular Epidemiology Unit, Institut Pasteur du Cambodge, 12 201 Phnom Penh, Cambodia.
17
Skaggs School of Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093.
18
Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, CA 92093.
19
Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, WA 98109.
20
Department of Global Health, University of Washington, Seattle, WA 98195.
21
Department of Biomedical Informatics and Medical Education, University of Washington, Seattle, WA 98195.
22
Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada.
23
Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104.
24
Computational Biology, School of Life Sciences, University of Dundee, DD1 5EH Dundee, United Kingdom.
25
Physics, School of Science and Engineering, University of Dundee, Dundee DD1 4HN, United Kingdom.
26
Structural Genomics Consortium, Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada.
27
Wellcome Centre for Anti-Infectives Research, Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, University of Dundee, DD1 5EH Dundee, United Kingdom; i.h.gilbert@dundee.ac.uk.

Abstract

Malaria and cryptosporidiosis, caused by apicomplexan parasites, remain major drivers of global child mortality. New drugs for the treatment of malaria and cryptosporidiosis, in particular, are of high priority; however, there are few chemically validated targets. The natural product cladosporin is active against blood- and liver-stage Plasmodium falciparum and Cryptosporidium parvum in cell-culture studies. Target deconvolution in P. falciparum has shown that cladosporin inhibits lysyl-tRNA synthetase (PfKRS1). Here, we report the identification of a series of selective inhibitors of apicomplexan KRSs. Following a biochemical screen, a small-molecule hit was identified and then optimized by using a structure-based approach, supported by structures of both PfKRS1 and C. parvum KRS (CpKRS). In vivo proof of concept was established in an SCID mouse model of malaria, after oral administration (ED90 = 1.5 mg/kg, once a day for 4 d). Furthermore, we successfully identified an opportunity for pathogen hopping based on the structural homology between PfKRS1 and CpKRS. This series of compounds inhibit CpKRS and C. parvum and Cryptosporidium hominis in culture, and our lead compound shows oral efficacy in two cryptosporidiosis mouse models. X-ray crystallography and molecular dynamics simulations have provided a model to rationalize the selectivity of our compounds for PfKRS1 and CpKRS vs. (human) HsKRS. Our work validates apicomplexan KRSs as promising targets for the development of drugs for malaria and cryptosporidiosis.

KEYWORDS:

cryptosporidiosis; malaria; tRNA synthetase

PMID:
30894487
PMCID:
PMC6452685
DOI:
10.1073/pnas.1814685116
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Conflict of interest statement: A patent relating to this work has been filed (PCT/GB2017/051809). F.-J.G. and L.M.S. are employees of GlaxoSmithKline and own shares of the company. M.B.J.-D. and I.A.-B. have shares in The Art of Discovery. Editor D.E.G. is a recent coauthor with two authors of this paper. He published a research article with M.A. in 2015. With E.A.W. he published two research articles in 2016, one research article in 2018, and coauthored a research article forthcoming in 2019. D.E.G. is a coinvestigator with E.A.W. on a 2012–2019 grant.

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