TRNA synthetase inhibitors

Protocol The test for the identification of aminoacyl-tRNA synthetase inhibitors requires the availability of precharged fMet-tRNA, Phe-tRNA, Thr-tRNA, and Ile-tRNA, which correspond to the amino acids present in the 027 peptide. The preparation of fMet-tRNA is described in the accompanying chapter by Milon et al., (2007), while the preparation of the other aminoacyl-tRNAs has been described previously. 

Beyer, D., Kroll, H. P., Endermann, R., Schiller, G., Siegel, S., Bauser, M., Pohlmann, J., Brands, M., Ziegelbauer, K., Haebich, D., Eymann, C., and Brotz-Oesterhelt, H. (2004). New class of bacterial phenylalanyl-tRNA synthetase inhibitors with high potency and broad-spectrum activity. Antimicrob. Agents Chemother. 48, 525—532. 

Jarvest, R.L. et al. 2003. Optimisation of aryl substitution leading to potent methionyl tRNA synthetase inhibitors with excellent gram-positive antibacterial activity. Bioorg. Med. Chem. Lett. 13, 665-668. 

Hmdle JG, O Neill AJ, Chopra I. Prospects for aminoacyl-tRNA synthetase inhibitors as new antimicrobial agents. Antimicrob. Agents Chemother. 2005 49 4821-4833. 

The biosynthesis of the macrolactam polyketide glycoside anti-tumour antibiotic vicenistatin L (1), including its vicenisamine moiety, has been studied using heavy atom-labelled precursors. The bicyclic branched-chain diaminohep-turonic acid derivative 2, a tyrosyl tRNA synthetase inhibitor of unknown absolute stereochemistry, has been isolated from a Microsmonospora species fermentation medium. ... 

Some simpler analogues of the bacterial tyrosyl tRNA synthetase inhibitor SB-219383 have been prepared. Reaction of the nitrone 160, prepared from L-arabinose by intramolecular alkylation of an oxime, with the anion of Ph2C = NCH2C02Et gave the separable isomers of 161. These were converted to 162 and its diastereoisomer, and compounds with opposite chirality in the piperidine ring were made from D-arabinose. Compound 162 had much greater bioactivity than the other three isomers, also displaying selectivity for the... 

Pohlmann, J. and Brotz-Oesterhelt, H. (2004) New aminoacyl-tRNA synthetase inhibitors as antibacterial agents. Curr. Drug Targets Infect. Disord. 4, 261-272. 

A three-component reaction of 2-diazoindan-l,3-dione (18), benzalde-hyde and substituted N-phenyhnaleimide gave in good yield a mixture of spirofuropyrroles 19 and 20 possessing three stereocenters in good yields (Scheme 6). These compounds 19 and 20 were reported to be potent tRNA synthetase inhibitors with IC50 of 0.6 and 0.004 M, respectively [68]. 

A recent example of the success of the bisubstrate, transition state design approach comes from the work of Pope and coworkers (Pope et al., 1998a-c Brown et al., 2000) on the design of inhibitors of bacterial isoleucyl tRNA synthetase... 

Figure 7.10 Chemical structure of SB-234764, a tight binding bisubstrate inhibitor of bacterial isoleucine tRNA synthetase.

Although aminoacyl-tRNA synthetases are necessary for protein synthesis in all tissues, their importance in chemical carcinogenesis is difficult to assess. Mutation induction by this pathway has been studied extensively (123), yet metabolic activation in a carcinogen-target tissue has not been demonstrated. The only exception is hepatic prolyl-tRNA synthetase activation of N-hydroxy-Trp-P-2 however, hepatic O-acetylation of this substrate also occurs to an appreciable extent (12). Further investigations involving the use of specific enzyme inhibitors would be helpful in addressing this problem. 

SB-203207 and SB-203208 -peptide-based inhibitors of isoieucyi tRNA synthetase... 

Direct Pathway Inhibitors of Glutaminyl-tRNA Synthetase and Asparaginyl-tRNA... 

Indirect Pathway Inhibitors of Glutamyl-tRNA Synthetase, Aspartyl-tRNA... 

Table 1 Inhibitors of glutaminyl-tRNA synthetase (GlnRS)...

Table 3 Inhibitors of glutamyl-tRNA synthetase (GluRS)...

Table 4 Inhibitors of aspartyl-tRNA synthetase (AspRS)...

R. Chenevert S. Bernier J. Lapointe, Inhibitors of Aminoacyl-tRNA Synthetases as Antibiotics and Tools for Structural and Mechanistic Studies. In Translation Mechanisms J. Lapointe, L. Brakier-Gingras, Eds. Eurekah.com/Landes Bioscience and Kluwer Academic/Plenum Publishers Georgetown TX, 2003 pp 416-428. 

Robert Chenevert is Professor of Organic Chemistry at Universite Laval, Quebec, Canada. He studied chemistry (B.Sc. and M.Sc.) at the Universite de Montreal. After receiving his Ph.D. in organic chemistry in 1975 at the Universite de Sherbrooke under the supervision of Professor Pierre Deslongchamps, he spent a postdoctoral year at Harvard (R. B. Woodward s group). His main research interest is the application of biocatalysts in asymmetric synthesis. He is also interested in the design of inhibitors of enzymes involved in the aminoacylation of tRNA (aminoacyl-tRNA synthetases and aminoacyl-tRNA amidotransferases). 

Mupirocin, pseudomonic acid, is a product of Pseudomonas fluorescens discovered by Fuller etal. It is an inhibitor of isoleucyl-transfer ribonucleic acid (isoleucyl-tRNA) synthetase. 

Pitram, S.M., Druzina, Z., Fokin, V.V., Schimmel, P, Sharpless, K.B. Inhibitors of tryptophanyl-tRNA synthetase from Plasmodium falciparum via in situ click chemistry. Abstracts of Papers, 232nd ACS National Meeting, San Francisco, CA, 10-14 September 2006. 

XY Yu, JM Hill, G Yu, W Wang, AF Kluge, P Wendler, P Gallant. Synthesis and structure-activity relationships of a series of novel thiazoles as inhibitors of amino-acyl-tRNA synthetases. Boorg Med Chem Lett 9 375-380, 1999. 

Nonetheless, there are several unexploited gene families that may provide additional multigene targets for inhibitors, such as the two-component signal transduction systems [32,51], tRNA synthetases [52], RNA polymerase sigma subunits [53,54], and the aminoacyl ligases of peptidoglycan biosynthesis [55],... 

Jarvest, R.L. et al. 2002. Nanomolar inhibitors of Staphylococcus aureus methionyl tRNA synthetase with potent antibacterial activity against gram-positive pathogens. J. Med. Chem. 45, 1959-1962. 

The indole derivative 12, a synthetic analogue of the antimicrobial natural product chuangxinmycin, is an inhibitor of bacterial tryptophanyl tRNA synthetase and displays antibacterial activity <2002BML3171>. 

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