Aminoacyl-tRNA synthetases as drug targets

2020 ◽  
pp. 321-350
Author(s):  
Maria Lukarska ◽  
Andrés Palencia
Keyword(s):  
Drug Targets ◽  
Trna Synthetases ◽  
Aminoacyl Trna Synthetases

scholarly journals Targeting Multiple Aminoacyl-tRNA Synthetases Overcomes the Resistance Liabilities Associated with Antibacterial Inhibitors Acting on a Single Such Enzyme

2016 ◽  
Vol 60 (10) ◽  
pp. 6359-6361 ◽  
Author(s):  
Christopher P. Randall ◽  
Dace Rasina ◽  
Aigars Jirgensons ◽  
Alex J. O'Neill
Keyword(s):  
Clinical Trials ◽  
High Frequency ◽  
Drug Targets ◽  
Clinical Utility ◽  
Bacterial Resistance ◽  
Antibacterial Drug ◽  
Resistance Development ◽  
Trna Synthetases ◽  
Aminoacyl Trna Synthetases ◽  
Potential Clinical Utility

ABSTRACTBacterial aminoacyl-tRNA synthetases (aaRSs) represent promising antibacterial drug targets. Unfortunately, the aaRS inhibitors that have to date reached clinical trials are subject to rapid resistance development through mutation, a phenomenon that limits their potential clinical utility. Here, we confirm the intuitively correct idea that simultaneous targeting of two different aaRS enzymes prevents the emergence of spontaneous bacterial resistance at high frequency, a finding that supports the development of multitargeted anti-aaRS therapies.

scholarly journals Drug targeting of aminoacyl-tRNA synthetases in Anopheles species and Aedes aegypti that cause malaria and dengue

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Soumyananda Chakraborti ◽  
Jyoti Chhibber-Goel ◽  
Amit Sharma
Keyword(s):  
Aedes Aegypti ◽  
Drug Targets ◽  
Viral Infections ◽  
Sequence Similarity ◽  
Mosquito Species ◽  
Physicochemical Characteristics ◽  
Computational Techniques ◽  
Trna Synthetases ◽  
Aminoacyl Trna Synthetases ◽  
Relationship Of

Abstract Background Mosquito-borne diseases have a devastating impact on human civilization. A few species of Anopheles mosquitoes are responsible for malaria transmission, and while there has been a reduction in malaria-related deaths worldwide, growing insecticide resistance is a cause for concern. Aedes mosquitoes are known vectors of viral infections, including dengue, yellow fever, chikungunya, and Zika. Aminoacyl-tRNA synthetases (aaRSs) are key players in protein synthesis and are potent anti-infective drug targets. The structure–function activity relationship of aaRSs in mosquitoes (in particular, Anopheles and Aedes spp.) remains unexplored. Methods We employed computational techniques to identify aaRSs from five different mosquito species (Anopheles culicifacies, Anopheles stephensi, Anopheles gambiae, Anopheles minimus, and Aedes aegypti). The VectorBase database (https://vectorbase.org/vectorbase/app) and web-based tools were utilized to predict the subcellular localizations (TargetP-2.0, UniProt, DeepLoc-1.0), physicochemical characteristics (ProtParam), and domain arrangements (PfAM, InterPro) of the aaRSs. Structural models for prolyl (PRS)-, and phenylalanyl (FRS)-tRNA synthetases—were generated using the I-TASSER and Phyre protein modeling servers. Results Among the vector species, a total of 37 (An. gambiae), 37 (An. culicifacies), 37 (An. stephensi), 37 (An. minimus), and 35 (Ae. aegypti) different aaRSs were characterized within their respective mosquito genomes. Sequence identity amongst the aaRSs from the four Anopheles spp. was > 80% and in Ae. aegypti was > 50%. Conclusions Structural analysis of two important aminoacyl-tRNA synthetases [prolyl (PRS) and phenylanalyl (FRS)] of Anopheles spp. suggests structural and sequence similarity with potential antimalarial inhibitor [halofuginone (HF) and bicyclic azetidine (BRD1369)] binding sites. This suggests the potential for repurposing of these inhibitors against the studied Anopheles spp. and Ae. aegypti.

scholarly journals Aminoacyl tRNA Synthetases as Malarial Drug Targets: A Comparative Bioinformatics Study

2018 ◽  
Author(s):  
Dorothy Wavinya Nyamai ◽  
Özlem Tastan Bishop
Keyword(s):  
Amino Acid ◽  
Drug Targets ◽  
Motif Discovery ◽  
Protein Translation ◽  
Trna Synthetase ◽  
Potential Drug ◽  
Multiple Sequence ◽  
Trna Synthetases ◽  
Aminoacyl Trna Synthetases ◽  
Potential Drug Targets

AbstractTreatment of parasitic diseases has been challenging due to the development of drug resistance by parasites, and thus there is need to identify new class of drugs and drug targets. Protein translation is important for survival of plasmodium and the pathway is present in all the life cycle stages of the plasmodium parasite. Aminoacyl tRNA synthetases are primary enzymes in protein translation as they catalyse the first reaction where an amino acid is added to the cognate tRNA. Currently, there is limited research on comparative studies of aminoacyl tRNA synthetases as potential drug targets. The aim of this study is to understand differences between plasmodium and human aminoacyl tRNA synthetases through bioinformatics analysis. Plasmodium falciparum, P. fragile, P. vivax, P. ovale, P. knowlesi, P. bergei, P. malariae and human aminoacyl tRNA synthetase sequences were retrieved from UniProt database and grouped into 20 families based on amino acid specificity. Despite functional and structural conservation, multiple sequence analysis, motif discovery, pairwise sequence identity calculations and molecular phylogenetic analysis showed striking differences between parasite and human proteins. Prediction of alternate binding sites revealed potential druggable sites in PfArgRS, PfMetRS and PfProRS at regions that were weakly conserved when compared to the human homologues. These differences provide a basis for further exploration of plasmodium aminoacyl tRNA synthetases as potential drug targets.

scholarly journals Molecular basis of the multifaceted functions of human leucyl-tRNA synthetase in protein synthesis and beyond

2020 ◽  
Vol 48 (9) ◽  
pp. 4946-4959
Author(s):  
Ru-Juan Liu ◽  
Tao Long ◽  
Hao Li ◽  
JingHua Zhao ◽  
Jing Li ◽  
...  
Keyword(s):  
Drug Development ◽  
Molecular Basis ◽  
Drug Targets ◽  
Trna Synthetase ◽  
Trna Synthetases ◽  
Aminoacyl Trna Synthetases ◽  
Assembly Mechanism ◽  
Mtorc1 Pathway ◽  
Pathogenic Microbes

Abstract Human cytosolic leucyl-tRNA synthetase (hcLRS) is an essential and multifunctional enzyme. Its canonical function is to catalyze the covalent ligation of leucine to tRNALeu, and it may also hydrolyze mischarged tRNAs through an editing mechanism. Together with eight other aminoacyl-tRNA synthetases (AaRSs) and three auxiliary proteins, it forms a large multi-synthetase complex (MSC). Beyond its role in translation, hcLRS has an important moonlight function as a leucine sensor in the rapamycin complex 1 (mTORC1) pathway. Since this pathway is active in cancer development, hcLRS is a potential target for anti-tumor drug development. Moreover, LRS from pathogenic microbes are proven drug targets for developing antibiotics, which however should not inhibit hcLRS. Here we present the crystal structure of hcLRS at a 2.5 Å resolution, the first complete structure of a eukaryotic LRS, and analyze the binding of various compounds that target different sites of hcLRS. We also deduce the assembly mechanism of hcLRS into the MSC through reconstitution of the entire mega complex in vitro. Overall, our study provides the molecular basis for understanding both the multifaceted functions of hcLRS and for drug development targeting these functions.

scholarly journals Aminoacyl-tRNA synthetases as drug targets in eukaryotic parasites

2014 ◽  
Vol 4 (1) ◽  
pp. 1-13 ◽  
Author(s):  
James S. Pham ◽  
Karen L. Dawson ◽  
Katherine E. Jackson ◽  
Erin E. Lim ◽  
Charisse Flerida A. Pasaje ◽  
...  
Keyword(s):  
Drug Targets ◽  
Trna Synthetases ◽  
Aminoacyl Trna Synthetases

scholarly journals Genetic Validation of Aminoacyl-tRNA Synthetases as Drug Targets in Trypanosoma brucei

2014 ◽  
Vol 13 (4) ◽  
pp. 504-516 ◽  
Author(s):  
Savitha Kalidas ◽  
Igor Cestari ◽  
Severine Monnerat ◽  
Qiong Li ◽  
Sandesh Regmi ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Trypanosoma Brucei ◽  
Drug Targets ◽  
Trna Synthetase ◽  
New Drugs ◽  
Sub Saharan Africa ◽  
Content Type ◽  
Trna Synthetases ◽  
Aminoacyl Trna Synthetases

ABSTRACT Human African trypanosomiasis (HAT) is an important public health threat in sub-Saharan Africa. Current drugs are unsatisfactory, and new drugs are being sought. Few validated enzyme targets are available to support drug discovery efforts, so our goal was to obtain essentiality data on genes with proven utility as drug targets. Aminoacyl-tRNA synthetases (aaRSs) are known drug targets for bacterial and fungal pathogens and are required for protein synthesis. Here we survey the essentiality of eight Trypanosoma brucei aaRSs by RNA interference (RNAi) gene expression knockdown, covering an enzyme from each major aaRS class: valyl-tRNA synthetase (ValRS) (class Ia), tryptophanyl-tRNA synthetase (TrpRS-1) (class Ib), arginyl-tRNA synthetase (ArgRS) (class Ic), glutamyl-tRNA synthetase (GluRS) (class 1c), threonyl-tRNA synthetase (ThrRS) (class IIa), asparaginyl-tRNA synthetase (AsnRS) (class IIb), and phenylalanyl-tRNA synthetase (α and β) (PheRS) (class IIc). Knockdown of mRNA encoding these enzymes in T. brucei mammalian stage parasites showed that all were essential for parasite growth and survival in vitro . The reduced expression resulted in growth, morphological, cell cycle, and DNA content abnormalities. ThrRS was characterized in greater detail, showing that the purified recombinant enzyme displayed ThrRS activity and that the protein localized to both the cytosol and mitochondrion. Borrelidin, a known inhibitor of ThrRS, was an inhibitor of T. brucei ThrRS and showed antitrypanosomal activity. The data show that aaRSs are essential for T. brucei survival and are likely to be excellent targets for drug discovery efforts.

scholarly journals tRNA Biology in Trypanosomes

2019 ◽  
Vol 73 (5) ◽  
pp. 395-405 ◽  
Author(s):  
Shikha Shikha ◽  
Rebecca Brogli ◽  
André Schneider ◽  
Norbert Polacek
Keyword(s):  
Drug Targets ◽  
Field Research ◽  
Model Systems ◽  
Biological Processes ◽  
Mitochondrial Trna ◽  
Trna Synthetases ◽  
Aminoacyl Trna Synthetases ◽  
Technological Advances ◽  
Trna Import ◽  
Medical Importance

Besides their medical importance, the parasitic protozoan Trypanosoma brucei and its relatives are experimentally highly accessible model systems for many cell biological processes. Trypanosomes are phylogenetically essentially unrelated to the popular model eukaryotes, such as yeast and animals, and thus show several unique features, many of which are connected to RNA. Here we review the tRNA biology of trypanosomes. Even though tRNAs were already discovered 60 years ago, owing to current technological advances in the field, research on tRNA biology has seen a Renaissance in recent years. First we discuss the extensive mitochondrial tRNA import process and the consequences it has for the parasite. Next we focus on trypanosomal aminoacyl-tRNA synthetases, some of which may be exploited as drug targets. Furthermore, we summarize what is known about trypanosomal tRNA modifications in both the cytosol and the mitochondrion. Finally, we provide an overview on the emerging field of tRNA-derived fragments and their possible function as translation regulators.

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