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

Kelly, Paul; Hadi-Nezhad, Fatemeh; Liu, Dennis Y.; Lawrence, Travis J.; Linington, Roger G.; Ibba, Michael; Ardell, David H.

doi:10.1371/journal.pntd.0007983

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

Journal Article · 27 February 2020 · PLoS Neglected Tropical Diseases (Online)

DOI: https://doi.org/10.1371/journal.pntd.0007983 · OSTI ID:1606044

Kelly, Paul ^[1]; Hadi-Nezhad, Fatemeh ^[2]; Liu, Dennis Y. ^[3];

^[4]; Linington, Roger G. ^[3];

^[1];

^[2]

The Ohio State Univ., Columbus, OH (United States)
Univ. of California, Merced, CA (United States)
Simon Fraser Univ., Burnaby, BC (Canada)
Univ. of California, Merced, CA (United States) ; Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)

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.

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Research Organization:: Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)

Sponsoring Organization:: USDOE

Grant/Contract Number:: AC05-00OR22725

OSTI ID:: 1606044

Journal Information:: PLoS Neglected Tropical Diseases (Online), Vol. 14, Issue 2; ISSN 1935-2735

Publisher:: Public Library of ScienceCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 11 works

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Chemogenomic profiling predicts antifungal synergies Jansen, Gregor; Lee, Anna Y.; Epp, Elias Molecular Systems Biology, Vol. 5, Issue 1 https://doi.org/10.1038/msb.2009.95	journal	January 2009
Chemical combination effects predict connectivity in biological systems Lehár, Joseph; Zimmermann, Grant R.; Krueger, Andrew S. Molecular Systems Biology, Vol. 3, Issue 1 https://doi.org/10.1038/msb4100116	journal	January 2007
ATP-directed capture of bioactive herbal-based medicine on human tRNA synthetase Zhou, Huihao; Sun, Litao; Yang, Xiang-Lei Nature, Vol. 494, Issue 7435 https://doi.org/10.1038/nature11774	journal	December 2012
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Accelerated evolution of resistance in multidrug environments Hegreness, M.; Shoresh, N.; Damian, D. Proceedings of the National Academy of Sciences, Vol. 105, Issue 37 https://doi.org/10.1073/pnas.0805965105	journal	September 2008
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Biochemical and physical characterization of an unmodified yeast phenylalanine transfer RNA transcribed in vitro. Sampson, J. R.; Uhlenbeck, O. C. Proceedings of the National Academy of Sciences, Vol. 85, Issue 4 https://doi.org/10.1073/pnas.85.4.1033	journal	February 1988
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RNA sequence analysis using covariance models Eddy, Sean R.; Durbin, Richard Nucleic Acids Research, Vol. 22, Issue 11 https://doi.org/10.1093/nar/22.11.2079	journal	January 1994
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tRNAscan-SE: A Program for Improved Detection of Transfer RNA Genes in Genomic Sequence Lowe, Todd M.; Eddy, Sean R. Nucleic Acids Research, Vol. 25, Issue 5 https://doi.org/10.1093/nar/25.5.955	journal	March 1997
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Visualizing bacterial tRNA identity determinants and antideterminants using function logos and inverse function logos Freyhult, E. Nucleic Acids Research, Vol. 34, Issue 3 https://doi.org/10.1093/nar/gkj478	journal	February 2006
GtRNAdb 2.0: an expanded database of transfer RNA genes identified in complete and draft genomes Chan, Patricia P.; Lowe, Todd M. Nucleic Acids Research, Vol. 44, Issue D1 https://doi.org/10.1093/nar/gkv1309	journal	December 2015
tRNAscan-SE On-line: integrating search and context for analysis of transfer RNA genes Lowe, Todd M.; Chan, Patricia P. Nucleic Acids Research, Vol. 44, Issue W1 https://doi.org/10.1093/nar/gkw413	journal	May 2016
An Antifungal Agent Inhibits an Aminoacyl-tRNA Synthetase by Trapping tRNA in the Editing Site Rock, F. L.; Mao, W.; Yaremchuk, A. Science, Vol. 316, Issue 5832 https://doi.org/10.1126/science.1142189	journal	June 2007
Changing the identity of a tRNA by introducing a G-U wobble pair near the 3' acceptor end McClain, W.; Foss, K. Science, Vol. 240, Issue 4853, p. 793-796 https://doi.org/10.1126/science.2452483	journal	May 1988
Aminoacyl-tRNA Synthesis Ibba, Michael; Söll, Dieter Annual Review of Biochemistry, Vol. 69, Issue 1 https://doi.org/10.1146/annurev.biochem.69.1.617	journal	June 2000
Unusual domain architecture of aminoacyl tRNA synthetases and their paralogs from Leishmania major Gowri, V. S.; Ghosh, Indira; Sharma, Amit BMC Genomics, Vol. 13, Issue 1 https://doi.org/10.1186/1471-2164-13-621	journal	January 2012
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