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Title: Targeting tRNA-synthetase interactions towards novel therapeutic discovery against eukaryotic pathogens

Abstract

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 targetingmore » multiple aaRSs should be less prone to the evolution of resistance than monotherapeutic or synergistic combination chemotherapies targeting only one aaRS.« less

Authors:
 [1];  [2];  [3]; ORCiD logo [4];  [3]; ORCiD logo [1]; ORCiD logo [2]
  1. The Ohio State Univ., Columbus, OH (United States)
  2. Univ. of California, Merced, CA (United States)
  3. Simon Fraser Univ., Burnaby, BC (Canada)
  4. Univ. of California, Merced, CA (United States) ; Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
Publication Date:
Research Org.:
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1606044
Grant/Contract Number:  
AC05-00OR22725
Resource Type:
Accepted Manuscript
Journal Name:
PLoS Neglected Tropical Diseases (Online)
Additional Journal Information:
Journal Name: PLoS Neglected Tropical Diseases (Online); Journal Volume: 14; Journal Issue: 2; Journal ID: ISSN 1935-2735
Publisher:
Public Library of Science
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Kelly, Paul, Hadi-Nezhad, Fatemeh, Liu, Dennis Y., Lawrence, Travis J., Linington, Roger G., Ibba, Michael, and Ardell, David H. Targeting tRNA-synthetase interactions towards novel therapeutic discovery against eukaryotic pathogens. United States: N. p., 2020. Web. doi:10.1371/journal.pntd.0007983.
Kelly, Paul, Hadi-Nezhad, Fatemeh, Liu, Dennis Y., Lawrence, Travis J., Linington, Roger G., Ibba, Michael, & Ardell, David H. Targeting tRNA-synthetase interactions towards novel therapeutic discovery against eukaryotic pathogens. United States. doi:https://doi.org/10.1371/journal.pntd.0007983
Kelly, Paul, Hadi-Nezhad, Fatemeh, Liu, Dennis Y., Lawrence, Travis J., Linington, Roger G., Ibba, Michael, and Ardell, David H. Thu . "Targeting tRNA-synthetase interactions towards novel therapeutic discovery against eukaryotic pathogens". United States. doi:https://doi.org/10.1371/journal.pntd.0007983. https://www.osti.gov/servlets/purl/1606044.
@article{osti_1606044,
title = {Targeting tRNA-synthetase interactions towards novel therapeutic discovery against eukaryotic pathogens},
author = {Kelly, Paul and Hadi-Nezhad, Fatemeh and Liu, Dennis Y. and Lawrence, Travis J. and Linington, Roger G. and Ibba, Michael and Ardell, David H.},
abstractNote = {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.},
doi = {10.1371/journal.pntd.0007983},
journal = {PLoS Neglected Tropical Diseases (Online)},
number = 2,
volume = 14,
place = {United States},
year = {2020},
month = {2}
}

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