Exploration of aminoacyl-tRNA synthetases from eukaryotic parasites for drug development
2022; Elsevier BV; Volume: 299; Issue: 3 Linguagem: Inglês
10.1016/j.jbc.2022.102860
ISSN1083-351X
Autores Tópico(s)Bacteriophages and microbial interactions
ResumoParasitic diseases result in considerable human morbidity and mortality. The continuous emergence and spread of new drug-resistant parasite strains is an obstacle to controlling and eliminating many parasitic diseases. Aminoacyl-tRNA synthetases (aaRSs) are ubiquitous enzymes essential for protein synthesis. The design and development of diverse small molecule, drug-like inhibitors against parasite-encoded and expressed aaRSs have validated this enzyme family as druggable. In this work, we have compiled the progress to date towards establishing the druggability of aaRSs in terms of their biochemical characterization, validation as targets, inhibitor development, and structural interpretation from parasites responsible for malaria (Plasmodium), lymphatic filariasis (Brugia, Wuchereria bancrofti), giardiasis (Giardia), toxoplasmosis (Toxoplasma gondii), leishmaniasis (Leishmania), cryptosporidiosis (Cryptosporidium), and trypanosomiasis (Trypanosoma). This work thus provides a robust framework for the systematic dissection of aaRSs from these pathogens and will facilitate the cross-usage of potential inhibitors to jump-start anti-parasite drug development. Parasitic diseases result in considerable human morbidity and mortality. The continuous emergence and spread of new drug-resistant parasite strains is an obstacle to controlling and eliminating many parasitic diseases. Aminoacyl-tRNA synthetases (aaRSs) are ubiquitous enzymes essential for protein synthesis. The design and development of diverse small molecule, drug-like inhibitors against parasite-encoded and expressed aaRSs have validated this enzyme family as druggable. In this work, we have compiled the progress to date towards establishing the druggability of aaRSs in terms of their biochemical characterization, validation as targets, inhibitor development, and structural interpretation from parasites responsible for malaria (Plasmodium), lymphatic filariasis (Brugia, Wuchereria bancrofti), giardiasis (Giardia), toxoplasmosis (Toxoplasma gondii), leishmaniasis (Leishmania), cryptosporidiosis (Cryptosporidium), and trypanosomiasis (Trypanosoma). This work thus provides a robust framework for the systematic dissection of aaRSs from these pathogens and will facilitate the cross-usage of potential inhibitors to jump-start anti-parasite drug development. Multiple eukaryotic parasites are responsible for the prevalence and continuous spread of more than a billion infections worldwide, thus burdening public health initiatives and the economy (1Bloom D.E. Cadarette D. Infectious disease threats in the twenty-first century: strengthening the global response.Front. Immunol. 2019; 10: 549Crossref PubMed Scopus (298) Google Scholar, 2Pham J.S. Dawson K.L. Jackson K.E. Lim E.E. Pasaje C.F. Turner K.E. et al.Aminoacyl-tRNA synthetases as drug targets in eukaryotic parasites.Int. J. Parasitol. Drugs Drug Resist. 2013; 4: 1-13Crossref PubMed Scopus (105) Google Scholar). Effective treatment and control of parasitic diseases needs the development of novel drugs as this process is further impeded by the periodic and inevitable development of drug resistance in parasites, and insecticide resistance in vectors. Such barriers to effective treatment could permit the resurgence of parasitic diseases, so there is an urgent need for novel anti-parasite drug scaffolds. Eukaryotic parasites can cause diverse diseases of varying severity in hosts, including both animals and humans. The parasites Plasmodium, Toxoplasma gondii, and Cryptosporidium of the phylum Apicomplexa are responsible for causing malaria, toxoplasmosis and cryptosporidiosis respectively (1Bloom D.E. Cadarette D. Infectious disease threats in the twenty-first century: strengthening the global response.Front. Immunol. 2019; 10: 549Crossref PubMed Scopus (298) Google Scholar, 2Pham J.S. Dawson K.L. Jackson K.E. Lim E.E. Pasaje C.F. Turner K.E. et al.Aminoacyl-tRNA synthetases as drug targets in eukaryotic parasites.Int. J. Parasitol. Drugs Drug Resist. 2013; 4: 1-13Crossref PubMed Scopus (105) Google Scholar, 3Seeber F. Steinfelder S. Recent advances in understanding apicomplexan parasites.F1000Research. 2016; 5: 1369Crossref Scopus (42) Google Scholar). Plasmodium species are responsible for the most acute forms of infection in humans after the proliferation and killing of red blood cells, with estimated 241 million malaria cases in 85 endemic countries (1Bloom D.E. Cadarette D. Infectious disease threats in the twenty-first century: strengthening the global response.Front. Immunol. 2019; 10: 549Crossref PubMed Scopus (298) Google Scholar, 2Pham J.S. Dawson K.L. Jackson K.E. Lim E.E. Pasaje C.F. Turner K.E. et al.Aminoacyl-tRNA synthetases as drug targets in eukaryotic parasites.Int. J. Parasitol. Drugs Drug Resist. 2013; 4: 1-13Crossref PubMed Scopus (105) Google Scholar, 3Seeber F. Steinfelder S. Recent advances in understanding apicomplexan parasites.F1000Research. 2016; 5: 1369Crossref Scopus (42) Google Scholar) (Fig. 1). Plasmodium vivax is more geographically widespread than Plasmodium falciparum and both are responsible for causing severe infections but only the former for relapses. T. gondii, an intracellular parasite, infects animals; however, they are also pathogenic in immunocompromised humans and can cause infections via food-borne illnesses (4Webster J.P. Toxoplasmosis of animals and humans.Parasites Vectors. 2010; 3: 112Crossref Google Scholar). This parasite is estimated to persist chronically in 25 to 30% of the global population (4Webster J.P. Toxoplasmosis of animals and humans.Parasites Vectors. 2010; 3: 112Crossref Google Scholar). After the human hosts ingest cysts, sporozoites are released. These sporozoites infect epithelial cells of the intestine, where the sporozoites develop into tachyzoites which multiply and infect more cells (Fig. 1). These stages together account for some symptoms of the disease (4Webster J.P. Toxoplasmosis of animals and humans.Parasites Vectors. 2010; 3: 112Crossref Google Scholar) (Fig. 1), and limited drugs are available for the treatment of toxoplasmosis. Cryptosporidium affects bovine calves by infecting epithelial cells of the intestine, causing gastrointestinal disease leading to severe and chronic diarrhea. It can further cause direct or indirect human exposure and have debilitating effects, especially in immunocompromised individuals (5Tzipori S. Widmer G. A hundred-year retrospective on cryptosporidiosis.Trends Parasitol. 2008; 24: 184-189Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). Cryptosporidium hominis and Cryptosporidium parvum are known to cause intestinal infections in humans (Fig. 1). Similarly, trypanosomatid parasites Trypanosoma and Leishmania of phylum Euglenozoa are two important parasites that cause human diseases (6Golding N. Review of "Trypanosomes and trypanosomiasis" by stefan magez and magdalena radwanska (Editors).Parasites Vectors. 2013; 6: 365Crossref Google Scholar, 7Mann S. Frasca K. Scherrer S. Henao-Martínez A.F. Newman S. Ramanan P. et al.A review of leishmaniasis: current knowledge and future directions.Curr. Trop. Med. Rep. 2021; 8: 121-132Crossref PubMed Scopus (0) Google Scholar). T. brucei causes African trypanosomiasis (sleeping sickness), where they proliferate inside the bloodstream and the human lymphatic system and subsequently affect the central nervous system often leading to fatality (Fig. 1). Trypanosoma cruzi causes the chronic and fatal Chagas disease which affects 6 to 7 million people worldwide. Leishmaniasis is one of the neglected tropical diseases (7Mann S. Frasca K. Scherrer S. Henao-Martínez A.F. Newman S. Ramanan P. et al.A review of leishmaniasis: current knowledge and future directions.Curr. Trop. Med. Rep. 2021; 8: 121-132Crossref PubMed Scopus (0) Google Scholar). The two Leishmania parasites Leishmania major and Leishmania donovani are responsible for human infections (Fig. 1) of varying severity, causing cutaneous leishmaniasis and visceral leishmaniasis (kala-azar) with an estimated 700,000 to 1 million new cases annually. Cutaneous leishmaniasis causes skin sores, while visceral leishmaniasis, the serious form of the disease, causes injury to internal organs (7Mann S. Frasca K. Scherrer S. Henao-Martínez A.F. Newman S. Ramanan P. et al.A review of leishmaniasis: current knowledge and future directions.Curr. Trop. Med. Rep. 2021; 8: 121-132Crossref PubMed Scopus (0) Google Scholar). There is a lack of effective drugs for these Trypanosomatid parasites, compounded by the threat of the emergence of resistance to available drugs. Other eukaryotic parasites with anaerobic metabolism, like Giardia (causes giardiasis), Trichomonas (trichomoniasis), and Entamoeba (amebiasis), are also a public health problem (8Cai W. Ryan U. Xiao L. Feng Y. Zoonotic giardiasis: an update.Parasitol. Res. 2021; 120: 4199-4218Crossref PubMed Scopus (28) Google Scholar). Although nitroimidazole drugs can be used, resistance remains a significant issue. The helminth parasites Brugia malayi and Wuchereria bancrofti cause lymphatic filariasis (elephantiasis) in humans, which is triggered by the immune system's reaction to adult worms and can lead to permanent disability (9Newman T.E. Juergens A.L. Filariasis. [Updated 2022 may 3].in: StatPearls [Internet]. StatPearls Publishing, Treasure island (FL)2022Google Scholar) (Fig. 1). In this work only Brugia parasite will be discussed. The treatment of such diverse parasitic diseases urgently requires the identification of robust drug targets and the continued development and design of novel drugs in order to tackle drug resistance. One such family of essential enzymes, the aminoacyl-tRNA synthetases (aaRSs), which tend to be conserved within different parasites, hold promise as a target for anti-parasite drug development. The aaRSs family of enzymes (also known as aminoacyl-tRNA ligases) are ubiquitous since they catalyze the linking of cognate amino acid that corresponds to the tRNA anticodon triplet (2Pham J.S. Dawson K.L. Jackson K.E. Lim E.E. Pasaje C.F. Turner K.E. et al.Aminoacyl-tRNA synthetases as drug targets in eukaryotic parasites.Int. J. Parasitol. Drugs Drug Resist. 2013; 4: 1-13Crossref PubMed Scopus (105) Google Scholar, 10Cusack S. Aminoacyl-tRNA synthetases.Curr. Opin. Struct. Biol. 1997; 7: 881-889Crossref PubMed Scopus (229) Google Scholar, 11Rubio Gomez M.A. Ibba M. Aminoacyl-tRNA synthetases.RNA. 2020; 26: 910-936Crossref PubMed Scopus (29) Google Scholar, 12Kwon N.H. Fox P.L. Kim S. Aminoacyl-tRNA synthetases as therapeutic targets.Nat. Rev. Drug Discov. 2019; 18: 629-650Crossref PubMed Scopus (110) Google Scholar, 13Schimmel P. The emerging complexity of the tRNA world: mammalian tRNAs beyond protein synthesis.Nat. Rev. Mol. Cell Biol. 2018; 19: 45-58Crossref PubMed Scopus (228) Google Scholar) (Fig. 2). The enzymatic reaction comprises of two steps; first, aaRS utilizes an ATP molecule to activate the cognate amino acid to generate an active aminoacyl-adenylate intermediate (amino acid-AMP) releasing pyrophosphate (PPi). Second, the cognate tRNA binds to the enzyme, which transfers the amino acid to the 3′ end of tRNA, releasing AMP (1Bloom D.E. Cadarette D. Infectious disease threats in the twenty-first century: strengthening the global response.Front. Immunol. 2019; 10: 549Crossref PubMed Scopus (298) Google Scholar, 10Cusack S. Aminoacyl-tRNA synthetases.Curr. Opin. Struct. Biol. 1997; 7: 881-889Crossref PubMed Scopus (229) Google Scholar, 11Rubio Gomez M.A. Ibba M. Aminoacyl-tRNA synthetases.RNA. 2020; 26: 910-936Crossref PubMed Scopus (29) Google Scholar, 12Kwon N.H. Fox P.L. Kim S. Aminoacyl-tRNA synthetases as therapeutic targets.Nat. Rev. Drug Discov. 2019; 18: 629-650Crossref PubMed Scopus (110) Google Scholar, 13Schimmel P. The emerging complexity of the tRNA world: mammalian tRNAs beyond protein synthesis.Nat. Rev. Mol. Cell Biol. 2018; 19: 45-58Crossref PubMed Scopus (228) Google Scholar). The resulting aminoacylated tRNA, an essential substrate for protein translation, is then transported by elongation factors to the ribosome to carry out protein synthesis (Fig. 2). Aminoacyl-tRNA synthetases also contain editing domains that ensure high fidelity of tRNA charging (12Kwon N.H. Fox P.L. Kim S. Aminoacyl-tRNA synthetases as therapeutic targets.Nat. Rev. Drug Discov. 2019; 18: 629-650Crossref PubMed Scopus (110) Google Scholar, 13Schimmel P. The emerging complexity of the tRNA world: mammalian tRNAs beyond protein synthesis.Nat. Rev. Mol. Cell Biol. 2018; 19: 45-58Crossref PubMed Scopus (228) Google Scholar). The aaRSs reduce errors by hydrolyzing misactivated amino acids (pretransfer to the tRNA) (Fig. 2) and misacylated tRNAs utilizing separate posttransfer-editing domains (11Rubio Gomez M.A. Ibba M. Aminoacyl-tRNA synthetases.RNA. 2020; 26: 910-936Crossref PubMed Scopus (29) Google Scholar). Aminoacyl-tRNA synthetases are thus essential enzymes for protein synthesis (i) for providing aminoacylated-tRNA with the cognate amino acid and (ii) for ensuring the accuracy of protein translation (Fig. 2). The aaRSs are also important for several other cellular processes beyond their catalytic roles, including regulation of transcription, biosynthesis of signal molecules, and mitochondrial RNA cleavage (10Cusack S. Aminoacyl-tRNA synthetases.Curr. Opin. Struct. Biol. 1997; 7: 881-889Crossref PubMed Scopus (229) Google Scholar, 11Rubio Gomez M.A. Ibba M. Aminoacyl-tRNA synthetases.RNA. 2020; 26: 910-936Crossref PubMed Scopus (29) Google Scholar, 12Kwon N.H. Fox P.L. Kim S. Aminoacyl-tRNA synthetases as therapeutic targets.Nat. Rev. Drug Discov. 2019; 18: 629-650Crossref PubMed Scopus (110) Google Scholar, 13Schimmel P. The emerging complexity of the tRNA world: mammalian tRNAs beyond protein synthesis.Nat. Rev. Mol. Cell Biol. 2018; 19: 45-58Crossref PubMed Scopus (228) Google Scholar). The aminoacyl-tRNA synthetases are categorized into two classes, I and II, on the basis of their structure, where class I aaRSs are mostly monomeric and contain the Rossman fold catalytic domain (2Pham J.S. Dawson K.L. Jackson K.E. Lim E.E. Pasaje C.F. Turner K.E. et al.Aminoacyl-tRNA synthetases as drug targets in eukaryotic parasites.Int. J. Parasitol. Drugs Drug Resist. 2013; 4: 1-13Crossref PubMed Scopus (105) Google Scholar, 12Kwon N.H. Fox P.L. Kim S. Aminoacyl-tRNA synthetases as therapeutic targets.Nat. Rev. Drug Discov. 2019; 18: 629-650Crossref PubMed Scopus (110) Google Scholar, 13Schimmel P. The emerging complexity of the tRNA world: mammalian tRNAs beyond protein synthesis.Nat. Rev. Mol. Cell Biol. 2018; 19: 45-58Crossref PubMed Scopus (228) Google Scholar) (Fig. 3). On the other hand, class II has a characteristic antiparallel beta-sheet fold surrounded by alpha-helices. Aminoacyl tRNA synthetases are prominently conserved in their catalytic domain due to their specific function; however, their sequence, structure, and function are seen to be relatively diverse across species. Structural and experimental data show that eukaryotic parasite aaRSs enzymes are excellent drug targets with multiple druggable sites; an ATP-binding pocket, the adjoining amino acid–binding pocket, and a tRNA recognition site (2Pham J.S. Dawson K.L. Jackson K.E. Lim E.E. Pasaje C.F. Turner K.E. et al.Aminoacyl-tRNA synthetases as drug targets in eukaryotic parasites.Int. J. Parasitol. Drugs Drug Resist. 2013; 4: 1-13Crossref PubMed Scopus (105) Google Scholar, 10Cusack S. Aminoacyl-tRNA synthetases.Curr. Opin. Struct. Biol. 1997; 7: 881-889Crossref PubMed Scopus (229) Google Scholar, 11Rubio Gomez M.A. Ibba M. Aminoacyl-tRNA synthetases.RNA. 2020; 26: 910-936Crossref PubMed Scopus (29) Google Scholar, 12Kwon N.H. Fox P.L. Kim S. Aminoacyl-tRNA synthetases as therapeutic targets.Nat. Rev. Drug Discov. 2019; 18: 629-650Crossref PubMed Scopus (110) Google Scholar, 13Schimmel P. The emerging complexity of the tRNA world: mammalian tRNAs beyond protein synthesis.Nat. Rev. Mol. Cell Biol. 2018; 19: 45-58Crossref PubMed Scopus (228) Google Scholar) (Fig. 4). The editing domains that are present on some aaRSs are additional targets for drugs. Some parasite aaRSs are localized to the cytosol (also simply referred to as the cytoplasm) and another subcellular organelle, apicoplast, a vestigial nonphotosynthetic plastid. The apicoplast is essential for parasite survival as it plays a crucial role in lipid metabolism in malaria parasites. The parasites are dependent on the apicoplast and on the mitochondria, and some aaRSs are dual localized in the cytosol and the apicoplast (2Pham J.S. Dawson K.L. Jackson K.E. Lim E.E. Pasaje C.F. Turner K.E. et al.Aminoacyl-tRNA synthetases as drug targets in eukaryotic parasites.Int. J. Parasitol. Drugs Drug Resist. 2013; 4: 1-13Crossref PubMed Scopus (105) Google Scholar, 3Seeber F. Steinfelder S. Recent advances in understanding apicomplexan parasites.F1000Research. 2016; 5: 1369Crossref Scopus (42) Google Scholar, 4Webster J.P. Toxoplasmosis of animals and humans.Parasites Vectors. 2010; 3: 112Crossref Google Scholar, 5Tzipori S. Widmer G. A hundred-year retrospective on cryptosporidiosis.Trends Parasitol. 2008; 24: 184-189Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 6Golding N. Review of "Trypanosomes and trypanosomiasis" by stefan magez and magdalena radwanska (Editors).Parasites Vectors. 2013; 6: 365Crossref Google Scholar, 7Mann S. Frasca K. Scherrer S. Henao-Martínez A.F. Newman S. Ramanan P. et al.A review of leishmaniasis: current knowledge and future directions.Curr. Trop. Med. Rep. 2021; 8: 121-132Crossref PubMed Scopus (0) Google Scholar, 8Cai W. Ryan U. Xiao L. Feng Y. Zoonotic giardiasis: an update.Parasitol. Res. 2021; 120: 4199-4218Crossref PubMed Scopus (28) Google Scholar, 9Newman T.E. Juergens A.L. Filariasis. [Updated 2022 may 3].in: StatPearls [Internet]. StatPearls Publishing, Treasure island (FL)2022Google Scholar, 10Cusack S. Aminoacyl-tRNA synthetases.Curr. Opin. Struct. Biol. 1997; 7: 881-889Crossref PubMed Scopus (229) Google Scholar, 11Rubio Gomez M.A. Ibba M. Aminoacyl-tRNA synthetases.RNA. 2020; 26: 910-936Crossref PubMed Scopus (29) Google Scholar, 12Kwon N.H. Fox P.L. Kim S. Aminoacyl-tRNA synthetases as therapeutic targets.Nat. Rev. Drug Discov. 2019; 18: 629-650Crossref PubMed Scopus (110) Google Scholar, 13Schimmel P. The emerging complexity of the tRNA world: mammalian tRNAs beyond protein synthesis.Nat. Rev. Mol. Cell Biol. 2018; 19: 45-58Crossref PubMed Scopus (228) Google Scholar). Thus, aaRSs in multiple organelles are potential drug targets in parasites.Figure 3Classification of aminoacyl-tRNA synthetases into class I and II and subclasses a, b and c. The parasites for which inhibitors have been developed against specific aaRSs are listed; Cp: Cryptosporidium parvum, Tb: Trypanosoma brucei, Tc: Trypanosoma cruzi, Pf: Plasmodium falciparum, Pv: Plasmodium vivax, Tg: Toxoplasma gondii, Gl: Giardia lamblia, Bm: Brugia malayi, Lm: Leishmania major, Ld: Leishmania donovani. aaRS, aminoacyl-tRNA synthetase.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Figure 4The potential druggable sites on aminoacyl-tRNA synthetases. The sites for likely interaction between aaRS (belonging to either class I or II) and a compound/inhibitor/drug which can inhibit the enzyme activity are highlighted; 1. ATP-binding site, 2. anticodon-binding site, 3. amino-acid–binding site, 4. editing site, and 5. auxiliary site.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Aminoacyl-tRNA synthetases are well-established drug targets for antibacterial and antifungal activities (14Bouz G. Zitko J. Inhibitors of aminoacyl-tRNA synthetases as antimycobacterial compounds: an up-to-date review.Bioorg. Chem. 2021; 110104806Crossref PubMed Scopus (10) Google Scholar, 15Nakama T. Nureki O. Yokoyama S. Structural basis for the recognition of isoleucyl-adenylate and an antibiotic, mupirocin, by isoleucyl-TRNA synthetase.J. Biol. Chem. 2001; 276: 47387-47393Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar, 16Rock F.L. Mao W. Yaremchuk A. Tukalo M. Crépin T. Zhou H. et al.An antifungal agent inhibits an aminoacyl-TRNA synthetase by trapping TRNA in the editing site.Science. 2007; 316: 1759-1761Crossref PubMed Scopus (501) Google Scholar). Several inhibitors have been developed, of which an antibiotic, the isoleucyl-tRNA synthetase (IleRS) inhibitor mupirocin, and the LeuRS inhibitor tavaborole, which is an antifungal, are approved for clinical treatment of methicillin-resistant Staphylococcus aureus and fungal-infective onychomycosis (14Bouz G. Zitko J. Inhibitors of aminoacyl-tRNA synthetases as antimycobacterial compounds: an up-to-date review.Bioorg. Chem. 2021; 110104806Crossref PubMed Scopus (10) Google Scholar, 15Nakama T. Nureki O. Yokoyama S. Structural basis for the recognition of isoleucyl-adenylate and an antibiotic, mupirocin, by isoleucyl-TRNA synthetase.J. Biol. Chem. 2001; 276: 47387-47393Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar, 16Rock F.L. Mao W. Yaremchuk A. Tukalo M. Crépin T. Zhou H. et al.An antifungal agent inhibits an aminoacyl-TRNA synthetase by trapping TRNA in the editing site.Science. 2007; 316: 1759-1761Crossref PubMed Scopus (501) Google Scholar). As drug targets, aaRSs have promising potential because the parasite, like all life forms, is reliant on protein translation. Moreover, due to the specific requirement of active and fast proliferation, parasites are sensitive towards disruption in the critical machinery of protein translation. In this work we summarize advancements in exploring parasite aminoacyl-tRNA synthetases as drug targets by consolidating experimental data on biochemical characterization, validation, inhibitor development, and three-dimensional structural dissections for aminoacyl-tRNA synthetases (in alphabetical order starting from alanyl-tRNA synthetase (AlaRS)) from seven eukaryotic pathogens Brugia spp., Cryptosporidium spp., Giardia spp., Leishmania spp., Plasmodium spp., T. gondii, and Trypanosoma spp. This work will facilitate research integration and provide new directions for antipathogen drug discovery. A single nuclear gene in the parasite Plasmodium encodes for AlaRS, giving rise to two proteins with different localizations, that is, the cytosol and the apicoplast (17Jackson K.E. Pham J.S. Kwek M. De Silva N.S. Allen S.M. Goodman C.D. et al.Dual targeting of aminoacyl-tRNA synthetases to the apicoplast and cytosol in Plasmodium falciparum.Int. J. Parasitol. 2012; 42: 177-186Crossref PubMed Scopus (0) Google Scholar, 18Khan S. Sharma A. Jamwal A. Sharma V. Pole A.K. Thakur K.K. et al.Uneven spread of cis- and trans-editing aminoacyl-tRNA synthetase domains within translational compartments of P.Falciparum. Sci. Rep. 2011; 1: 188Crossref PubMed Scopus (0) Google Scholar). Plasmodium AlaRS also contains a second active site with editing activity since glycine and serine are the most common mischarging events due to their similar size (19Sokabe M. Okada A. Yao M. Nakashima T. Tanaka I. Molecular basis of alanine discrimination in editing site.Proc. Natl. Acad. Sci. U. S. A. 2005; 102: 11669-11674Crossref PubMed Scopus (49) Google Scholar). AlaRS presents an opportunity to target aminoacylation and the editing activities occurring in two distinct parasite compartments. Several potential P. falciparum AlaRS inhibitors were screened in silico using homology models, revealing one compound A5, (4-{2-nitro-1-propenyl}-1,2-benzenediol), that was validated to inhibit parasite growth at micromolar levels while producing sparse cytotoxicity (Table 1) (Figure 3, Figure 4, Figure 5) (18Khan S. Sharma A. Jamwal A. Sharma V. Pole A.K. Thakur K.K. et al.Uneven spread of cis- and trans-editing aminoacyl-tRNA synthetase domains within translational compartments of P.Falciparum. Sci. Rep. 2011; 1: 188Crossref PubMed Scopus (0) Google Scholar). In another study, a pre-validated MNP library (marine natural product; a specific group of bacterial extract prefractions with demonstrated activity against Leishmania) was used and four potential L. major AlaRS inhibitors decreased the overall tRNA-AlaRS aminoacylation activity (20Kelly P. Hadi-Nezhad F. Liu D.Y. Lawrence T.J. Linington R.G. Ibba M. et al.Targeting tRNA-synthetase interactions towards novel therapeutic discovery against eukaryotic pathogens.PLoS Negl. Trop. Dis. 2020; 14e0007983Crossref Scopus (8) Google Scholar, 21Schulze C.J. Bray W.M. Woerhmann M.H. Stuart J. Lokey R.S. Linington R.G. "Function-first" lead discovery: mode of action profiling of natural product libraries using image-based screening.Chem. Biol. 2013; 20: 285-295Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). The three promising mixes (1881C, 2059D, and 2096D) affected aminoacylation with inhibition ranging from 80% to 99% (Table 1). Interestingly, cross-reactivity is also seen with T. cruzi AlaRS, which indicates a broad-spectrum potential and no effect on the human homolog (20Kelly P. Hadi-Nezhad F. Liu D.Y. Lawrence T.J. Linington R.G. Ibba M. et al.Targeting tRNA-synthetase interactions towards novel therapeutic discovery against eukaryotic pathogens.PLoS Negl. Trop. Dis. 2020; 14e0007983Crossref Scopus (8) Google Scholar). AlaRS is yet to be explored in four of the seven pathogens Brugia, Cryptosporidium, Giardia and Toxoplasma, discussed in this review (20Kelly P. Hadi-Nezhad F. Liu D.Y. Lawrence T.J. Linington R.G. Ibba M. et al.Targeting tRNA-synthetase interactions towards novel therapeutic discovery against eukaryotic pathogens.PLoS Negl. Trop. Dis. 2020; 14e0007983Crossref Scopus (8) Google Scholar). The first three-dimensional structure of parasite AlaRS remains to be determined; however, similar to Plasmodium, homology-modeled structures from bacteria and fungi could be explored for in silico docking.Table 1Inhibitors developed for aminoacyl-tRNA synthetases against eukaryotic parasites up till June 2022aaRSsInhibitor(s)ParasiteBinding mechanismReferenceAlaRSA3; A5Plasmodium falciparumActive site aPredicted binding mechanism: The inhibitor has been experimentally validated to inhibit aminoacylation/pretransfer editing activity of the aaRS enzyme and thus is predicted to bind at the active/pretransfer-editing site. However, structural interpretation or validation is not available.Khan et al., 2011 (18Khan S. Sharma A. Jamwal A. Sharma V. Pole A.K. Thakur K.K. et al.Uneven spread of cis- and trans-editing aminoacyl-tRNA synthetase domains within translational compartments of P.Falciparum. Sci. Rep. 2011; 1: 188Crossref PubMed Scopus (0) Google Scholar)Natural marine product library (1881C, 2059D, and 2096D)Leishmania majorTrypanosoma cruziActive site aPredicted binding mechanism: The inhibitor has been experimentally validated to inhibit aminoacylation/pretransfer editing activity of the aaRS enzyme and thus is predicted to bind at the active/pretransfer-editing site. However, structural interpretation or validation is not available.Kelly et al., 2020 (20Kelly P. Hadi-Nezhad F. Liu D.Y. Lawrence T.J. Linington R.G. Ibba M. et al.Targeting tRNA-synthetase interactions towards novel therapeutic discovery against eukaryotic pathogens.PLoS Negl. Trop. Dis. 2020; 14e0007983Crossref Scopus (8) Google Scholar)ArgRSheminPlasmodium falciparumNot knownJain et al., 2016 (22Jain V. Yogavel M. Sharma A. Dimerization of arginyl-tRNA synthetase by free heme drives its inactivation in plasmodium falciparum.Structure. 2016; 24: 1476-1487Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar)AsnRSVariolin BBrugia malayiActive site aPredicted binding mechanism: The inhibitor has been experimentally validated to inhibit aminoacylation/pretransfer editing activity of the aaRS enzyme and thus is predicted to bind at the active/pretransfer-editing site. However, structural interpretation or validation is not available.Sukuru et al., 2006 (27Sukuru S.C. Crepin T. Milev Y. Marsh L.C. Hill J.B. Anderson R.J. et al.Discovering new classes of Brugia malayi asparaginyl-tRNA synthetase inhibitors and relating specificity to conformational change.J. Comput. Aided Mol. Des. 2006; 20: 159-178Crossref PubMed Scopus (37) Google Scholar)Natural product extracts (L-aspartate-B-hydroxamateBrugia malayiPretransfer editing site aPredicted binding mechanism: The inhibitor has been experimentally validated to inhibit aminoacylation/pretransfer editing activity of the aaRS enzyme and thus is predicted to bind at the active/pretransfer-editing site. However, structural interpretation or validation is not available.Danel et al., 2011 (28Danel F. Caspers P. Nuoffer C. Härtlein M. Kron M.A. Page M.G. Asparaginyl-tRNA synthetase pre-transfer editing assay.Curr. Drug Discov. Technol. 2011; 8: 66-75Crossref PubMed Scopus (0) Google Scholar)TAM B (from Streptomyces sp. 17944 extracts)Brugia malayiPretransfer editing site aPredicted binding mechanism: The inhibitor has been experimentally validated to inhibit aminoacylation/pretransfer editing activity of the aaRS enzyme and thus is predicted to bind at the active/pretransfer-editing site. However, structural interpretation or validation is not available.Yu et al., 2011 (29Yu Z. Vodanovic-Jankovic S. Ledeboer N. Huang S.X. Rajski S.R. Kron M. et al.Tirandamycins from Streptomyces sp. 17944 inhibiting the parasite Brugia malayi asparagine tRNA synthetase.Org. Lett. 2011; 13: 2034-2037Crossref PubMed Scopus (51) Google Scholar)WS9326D (from Streptomyces sp. 9078 extracts)Brugia malayiPretransfer editing site aP
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