The chemical element boron is part of what makes Millennium Pharmaceutical Inc.'s multiple myeloma drug Velcade (bortezomib) a success; a boron atom helps Velcade inhibit the proteasome, leading to apoptosis of cancer cells.
In the June 22, 2007, issue of Science, researchers from Palo Alto, Calif.-based biotech firm Anacor Pharmaceuticals report on a different mechanism for boron-based chemistry's utility in another area: anti-infectives.
Anacor is focused on boron-based chemistry, and currently has three compounds in clinical development in various dermatological indications. In their paper, researchers investigated the mechanism of action of their lead compound. AN2690 is in Phase II trials for the treatment of onychomycosis, a fungal infection of the nails and nail bed. It is partnered with Schering-Plough Corp. (See BioWorld Today, Feb. 5, 2007.)
The researchers deciphered how AN2690 works by initially looking at those cases where it doesn't: AN2690-resistant strains of yeast, which is biologically similar to fungi. In almost all of the strains they investigated, the resistance mutation turned out to be located in the gene for a transfer-RNA synthetase. Crystallography studies of target-bound AN2690 then allowed them to work out the mechanism in greater detail.
Transfer RNAs, which add amino acids to a protein during synthesis, are "proven drug targets," Anacor's head of discovery biology, Dickon Alley, told BioWorld Today. Tetracyclines, for example, halt protein synthesis by blocking transfer RNAs from adding amino acids to a half-finished protein.
But transfer RNAs have two active sites, and only one of them has been getting pharmaceutical attention to date: "All big pharma has looked at is the synthetic site — they've never looked at the editing site," said Alley, who is the paper's senior author.
To make sure that it is the right amino acid being added to the chain, most tRNAs have two distinct functional sites: one site that binds the amino acid, and another that double checks or edits to make sure the correct amino acid is bound. But crystallography studies revealed that AN2690 affects precisely that editing site of one specific tRNA, leucyl-tRNA synthetase, by trapping bound leucine in the editing site, which makes its transfer impossible and thus halts protein synthesis.
Boron is able to trap the activated leucine because of the characteristics of its electrons. In the case of AN2690, the compound forms two bonds with its target. That is in contrast to Velcade, in which boron takes the form of boronic acid and forms only one bond.
Anacor currently is focused on dermatologic indications. But the results published in Science suggest that boron-containing compounds could be useful to target systemic bacterial infections, and the company is planning to move into the antibacterial arena.
"Drug-resistant bacteria are a large and growing problem in the hospital and in the community, which makes the discovery of novel antibiotics a public health necessity," said David Perry, Anacor's CEO. "We believe that our approach may hold great promise in the development of these needed therapies."