Targeting tRNA-synthetase interactions towards novel therapeutic discovery against eukaryotic pathogens.
The development of chemotherapies against eukaryotic pathogens is especially challenging because of both the evolutionary conservation of drug targets between host and parasite, and the evolution of strain-dependent drug resistance. There is a strong need for new nontoxic drugs with broad-spectrum a...
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ftdoajarticles:oai:doaj.org/article:2bcd2afbb04e4533845b81c890cb991e 2023-05-15T15:09:46+02:00 Targeting tRNA-synthetase interactions towards novel therapeutic discovery against eukaryotic pathogens. Paul Kelly Fatemeh Hadi-Nezhad Dennis Y Liu Travis J Lawrence Roger G Linington Michael Ibba David H Ardell 2020-02-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0007983 https://doaj.org/article/2bcd2afbb04e4533845b81c890cb991e EN eng Public Library of Science (PLoS) https://doi.org/10.1371/journal.pntd.0007983 https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0007983 https://doaj.org/article/2bcd2afbb04e4533845b81c890cb991e PLoS Neglected Tropical Diseases, Vol 14, Iss 2, p e0007983 (2020) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2020 ftdoajarticles https://doi.org/10.1371/journal.pntd.0007983 2022-12-31T07:51:24Z The development of chemotherapies against eukaryotic pathogens is especially challenging because of both the evolutionary conservation of drug targets between host and parasite, and the evolution of strain-dependent drug resistance. There is a strong need for new nontoxic drugs with broad-spectrum activity against trypanosome parasites such as Leishmania and Trypanosoma. A relatively untested approach is to target macromolecular interactions in parasites rather than small molecular interactions, under the hypothesis that the features specifying macromolecular interactions diverge more rapidly through coevolution. We computed tRNA Class-Informative Features in humans and independently in eight distinct clades of trypanosomes, identifying parasite-specific informative features, including base pairs and base mis-pairs, that are broadly conserved over approximately 250 million years of trypanosome evolution. Validating these observations, we demonstrated biochemically that tRNA:aminoacyl-tRNA synthetase (aaRS) interactions are a promising target for anti-trypanosomal drug discovery. From a marine natural products extract library, we identified several fractions with inhibitory activity toward Leishmania major alanyl-tRNA synthetase (AlaRS) but no activity against the human homolog. These marine natural products extracts showed cross-reactivity towards Trypanosoma cruzi AlaRS indicating the broad-spectrum potential of our network predictions. We also identified Leishmania major threonyl-tRNA synthetase (ThrRS) inhibitors from the same library. We discuss why chemotherapies targeting multiple aaRSs should be less prone to the evolution of resistance than monotherapeutic or synergistic combination chemotherapies targeting only one aaRS. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLOS Neglected Tropical Diseases 14 2 e0007983 |
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Open Polar |
collection |
Directory of Open Access Journals: DOAJ Articles |
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ftdoajarticles |
language |
English |
topic |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
spellingShingle |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Paul Kelly Fatemeh Hadi-Nezhad Dennis Y Liu Travis J Lawrence Roger G Linington Michael Ibba David H Ardell Targeting tRNA-synthetase interactions towards novel therapeutic discovery against eukaryotic pathogens. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
The development of chemotherapies against eukaryotic pathogens is especially challenging because of both the evolutionary conservation of drug targets between host and parasite, and the evolution of strain-dependent drug resistance. There is a strong need for new nontoxic drugs with broad-spectrum activity against trypanosome parasites such as Leishmania and Trypanosoma. A relatively untested approach is to target macromolecular interactions in parasites rather than small molecular interactions, under the hypothesis that the features specifying macromolecular interactions diverge more rapidly through coevolution. We computed tRNA Class-Informative Features in humans and independently in eight distinct clades of trypanosomes, identifying parasite-specific informative features, including base pairs and base mis-pairs, that are broadly conserved over approximately 250 million years of trypanosome evolution. Validating these observations, we demonstrated biochemically that tRNA:aminoacyl-tRNA synthetase (aaRS) interactions are a promising target for anti-trypanosomal drug discovery. From a marine natural products extract library, we identified several fractions with inhibitory activity toward Leishmania major alanyl-tRNA synthetase (AlaRS) but no activity against the human homolog. These marine natural products extracts showed cross-reactivity towards Trypanosoma cruzi AlaRS indicating the broad-spectrum potential of our network predictions. We also identified Leishmania major threonyl-tRNA synthetase (ThrRS) inhibitors from the same library. We discuss why chemotherapies targeting multiple aaRSs should be less prone to the evolution of resistance than monotherapeutic or synergistic combination chemotherapies targeting only one aaRS. |
format |
Article in Journal/Newspaper |
author |
Paul Kelly Fatemeh Hadi-Nezhad Dennis Y Liu Travis J Lawrence Roger G Linington Michael Ibba David H Ardell |
author_facet |
Paul Kelly Fatemeh Hadi-Nezhad Dennis Y Liu Travis J Lawrence Roger G Linington Michael Ibba David H Ardell |
author_sort |
Paul Kelly |
title |
Targeting tRNA-synthetase interactions towards novel therapeutic discovery against eukaryotic pathogens. |
title_short |
Targeting tRNA-synthetase interactions towards novel therapeutic discovery against eukaryotic pathogens. |
title_full |
Targeting tRNA-synthetase interactions towards novel therapeutic discovery against eukaryotic pathogens. |
title_fullStr |
Targeting tRNA-synthetase interactions towards novel therapeutic discovery against eukaryotic pathogens. |
title_full_unstemmed |
Targeting tRNA-synthetase interactions towards novel therapeutic discovery against eukaryotic pathogens. |
title_sort |
targeting trna-synthetase interactions towards novel therapeutic discovery against eukaryotic pathogens. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2020 |
url |
https://doi.org/10.1371/journal.pntd.0007983 https://doaj.org/article/2bcd2afbb04e4533845b81c890cb991e |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 14, Iss 2, p e0007983 (2020) |
op_relation |
https://doi.org/10.1371/journal.pntd.0007983 https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0007983 https://doaj.org/article/2bcd2afbb04e4533845b81c890cb991e |
op_doi |
https://doi.org/10.1371/journal.pntd.0007983 |
container_title |
PLOS Neglected Tropical Diseases |
container_volume |
14 |
container_issue |
2 |
container_start_page |
e0007983 |
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1766340894442651648 |