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Researchers Devise New Compound to Treat Fungal Infections

Researchers have formed a new compound AN2690, that might help to attack hard-to-treat fungal infection in nails by blocking an enzyme crucial for the protein synthesis of fungal pathogens.

The study was conducted by a team of researchers including Dickon Alley and Stephen Cusack at Anacor Pharmaceuticals Inc., California, and the European Molecular Biology Laboratory (EMBL) outstation in Grenoble, France.

AN2690 interferes with an enzyme called leucyl-tRNA synthetase, which is involved in translation, one of the last steps in the process of turning a gene's DNA code into a protein.

The process begins when the cell makes an RNA version of the gene's code, called messenger RNA. Ribosomes, the cell's protein synthesis machinery, then translate the messenger RNA into protein by stitching together the amino acids in the order specified by the message. This requires the help of molecules called tRNAs, which link the code of the messenger RNA to the correct amino acid.

Leucyl-tRNA synthetase is one of a group of enzymes called aminoacyl-tRNA synthetases that attach the correct amino acid to each tRNA. Some of these enzymes have two main functional parts that link the amino acid to the tRNA, and a separate editing site that proofreads this process and removes wrongly added amino acids.

As part of the study, to find out how exactly AN2690 blocks leucyl-tRNA synthetase, researchers generated crystals of the enzyme bound to tRNA in the presence of AN2690 and examined them with high-intensity X-ray source.

Researchers found that AN2690 stuck in the editing site of the enzyme where it made a very strong bond to the end of the tRNA, trapping it on the enzyme. This stopped the enzyme working and thus blocked protein synthesis, killing the fungal cell.

"We have discovered a new compound that has the potential to treat common chronic nail infections caused by fungi," Alley said.

The mechanism crucially depended on a boron atom that is part of AN2690, which is needed to link the compound to the tRNA.

"We are now working towards finding related antibacterial compounds that could help counter the problem of antibiotic resistance," Cusack said.

The findings of the study were published in the June issue of Science.


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