Chemical libraries

Encoded self-assembling chemical libraries. Melkko, S. et al. Nature Biotechnol. 18 April 2004 (doi:10.1038/nbt961)

The isolation of molecules capable of high-affinity and specific binding to biological targets is a central problem in drug discovery. This paper describes the use of encoded self-assembling chemical (ESAC) libraries for the identification of molecules that bind macromolecular targets. ESAC technology uses libraries of organic molecules linked to individual oligonucleotides that mediate the self-assembly of the library and provide a code associated with each organic molecule. After panning ESAC libraries on the biomolecular target of interest, the 'binding code' of the selected compounds can be 'decoded' by a number of experimental techniques. This technology was demonstrated by the affinity maturation (>40-fold) of binding molecules to human serum albumin and bovine carbonic anhydrase.

Inflammatory bowel disease

Functional variants of OCTN cation transporter genes are associated with Crohn's disease. Peltekova, V. D. Nature Genet. 11 April 2004 (doi:10.1038/ng1339)

Genetic variation in DLG5 is associated with inflammatory bowel disease. Stoll, M. Nature Genet. 11 April 2004 (doi:10.1038/ng1345)

Two recent studies have identified genes associated with susceptibility to the inflammatory bowel diseases Crohn's disease (CD) and ulcerative colitis (UC). Variants of two neighbouring genes on chromosome 5 are associated with susceptibility to CD. These genes encode related proteins whose function is to transport small molecules across cell membranes. The variant of one of the genes results in a protein with altered transport properties; the other variant alters a binding site for a factor that controls expression levels of the second gene. A different gene on chromosome 10 is associated with susceptibility to both UC and CD. This gene encodes a protein involved in maintaining the integrity of cellular sheets like the one that forms the lining of the intestine.

Antibacterial drugs

Structural insight into arginine degradation by arginine deaminase, an antibacterial and parasite drug target. Galkin, A. et al. J. Biol. Chem. 279, 14001–14008 (2004)

L-Arginine deaminase (ADI) is involved in the first step of the most widespread anaerobic route of arginine degradation. Its important function in both pathogenic protozoa and bacteria, in addition to its absence in higher eukaryotes, make the enzyme an attractive therapeutic target for the treatment of bacterial and parasitic infections. The crystal structure of ADI from Pseudomonas aeruginosa has been solved at 2.45 Å resolution. On the basis of the structure, the authors propose an ADI catalytic mechanism.