Anacor's boron-based drug stops the rot
treat fungal infections, and could also prove invaluable in the
effort to counter antibacterial drug resistance.
Scientists from the young US pharma firm Anacor developed AN2690, the first in a new class of antibiotics that contain a crucial boron atom. Together with a team from the European Molecular Biology Laboratory (EMBL) outstation in Grenoble, France, the researchers have now discovered exactly how the drug works. "We have discovered a new compound that has the potential to treat common chronic nail infections caused by fungi [onychomycosis]," said Dickon Alley, a researcher at Anacor Pharmaceuticals. "Now that we know how AN2690 works, the same approach could be adapted to target other aminoacyl-tRNA synthetases with editing sites and also other pathogenic microbes," said Stephen Cusack, Head of EMBL. "We are now working towards finding related antibacterial compounds that could help counter the problem of antibiotic resistance." Alley explained that the compound kills fungi by blocking their ability to make proteins. It does this by blocking 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 (mRNA). Ribosomes, the cell's protein synthesis machinery, then translate the mRNA into protein by stitching together the amino acids in the order specified by the message. This requires the help of molecules called transfer RNAs (tRNAs), which link the mRNA 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, or active sites: a site that links the amino acid to the tRNA, and a separate editing site that proofreads this process and removes wrongly added amino acids. To find out how exactly AN2690 blocks leucyl-tRNA synthetase Stephen Cusack, Head of EMBL Grenoble, and his team generated crystals of the enzyme bound to tRNA in the presence of AN2690. They then used X-rays to examine the structure of the complex. Cusack and his colleagues found that AN2690 sticks in the editing site of the enzyme where it makes a very strong bond to the end of the tRNA, trapping it on the enzyme. This stops the enzyme working and thus blocks protein synthesis, killing the fungal cell. The mechanism crucially depends on a boron atom that is part of AN2690, which is needed to link the compound to the tRNA. According to Anacor, it is the first time that scientists have described such a mechanism, suggesting boron containing compounds as a promising new class of drug candidates. The drug itself is currently in Phase II trials. The pharma industry in general is watching this approach keenly. In February, Schering-Plough paid over $575m ($40m upfront) to gain the exclusive global rights to AN2690 from Anacor. Historically, several other pharma companies have also shown an interest in aminoacyl-tRNA synthetase inhibitors. Curiously, as far back as 1999, AstraZeneca (then plain Zeneca), had a patent issued for an assay to identify potential drugs aimed at this target. However, whether this technology bared any fruit is unclear. In June 2006, AZ announced that its "genomic approach to anti-bacterials is yielding its first candidates". The company was referring to AZD1279, a bactericidal antibiotic from a new chemical class, which has showed good in vitro activity against resistant organisms including Streptococcus pneumoniae. AZ said at the time that the drug would enter Phase I clinical trials for respiratory infections in 2006. The target for this drug was never disclosed however, and a spokesperson for AZ told DrugResearcher.com that the drug has now been scrapped, although she couldn't say why this decision had been taken. Cubist Pharmaceuticals is, or at least was, interested in this target as well, having penned an academic article called 'Aminoacyl tRNA synthetases as targets for new anti-infectives' in a 1999 edition of the Federation of American Societies for Experimental Biology journal. However, again, there is no mention of this target on their website and the company was unable to confirm whether this target was still being investigated. Why Anacor's drug seems to be enjoying success where others have failed is not known. However, it is good news for onychomycosis sufferers, the patients AN2690 aims to treat initially. It affects approximately 7 to 10 per cent of the US population, including 48 percent of those over age 70. More than 90 percent of those cases are caused by two specific fungi: Trichophyton rubrum and Trichophyton mentagrophytes. However, current treatments are limited, according to Anacor. Existing topical treatments only succeed in 12 per cent of cases, despite sales accounting for $300m (€223m). Whereas systemic treatments are more effective (in around half of all cases), they have known toxicity. Novartis' Lamisil (terbinafine) generated sales of $978m in 2006 but the same drug has, in rare cases caused liver failure. These have resulted in the need for a transplant and even death, although the relationship between the liver problems and the drug is "uncertain", according to the drug's approved label, as the patients' involved had serious pre-existing liver conditions.