Transport Proteins

Structure and mechanism of the lactose permease of Escherichia coli. Abramson, J. et al. Science 301, 610–615 (2003).

Structure and mechanism of the glycerol-3-phosphate transporter of Escherichia coli. Huang, Y. et al. Science 301, 616–620 (2003).

Membrane transport proteins have been shown to have important roles in depression, stroke and diabetes, and are the targets of widely used drugs, such as fluoxetine and omeprazole. However, structural information on these proteins, which could aid in future drug design, has been lacking owing to the challenges associated with obtaining suitable crystals for X-ray structure determination. These two papers report the first crystal structures of proteins from the major facilitator superfamily, the largest group of secondary membrane transporters.

Anticancer Drugs

Functionalized glycomers as growth inhibitors and inducers of apoptosis in human glioblastoma cells. Hanessian, S. et al. J. Med. Chem. (2003) July 16 (doi:10.1021/jm0205853).

Glioblastomas are brain tumours that have a very poor prognosis, as they are often resistant to traditional drugs and their high migratory potential in the central nervous system precludes surgical removal. Hanessian et al. show that monosaccharide derivatives can inhibit the growth and/or induce apoptosis of human glioblastoma cells, and so represent a new class of molecules that are potentially able to control the progression of brain tumours.

Neurodegenerative Disease

Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Aβ and synaptic dysfunction. Oddo, S. et al. Neuron 39, 409–421 (2003)

Alzheimer's disease is characterized by two hallmark lesions: neuritic plaques containing amyloid-β, and neurofibrillary tangles composed of aggregates of hyperphosphorylated tau protein. Oddo et al. have created a mouse model that recapitulates these salient features of Alzheimer's disease, which will be valuable for evaluating the efficacy of therapies in mitigating the neurodegenerative effects mediated by both signature lesions.

High-Throughput Screeing

Effects of detergent on “promiscuous” inhibitors. Ryan, A. J. et al. J. Med. Chem. 46, 3448–3551 (2003).

The term 'promiscuous inhibitor' has been used to describe compounds that inhibit a range of unrelated enzymes through an inhibition mechanism that involves the formation of aggregates, rather than the binding of individual molecules, which are therefore unlikely to be good starting points for drug discovery programmes. Ryan et al. show that promiscuous inhibitors can be differentiated from classical inhibitors by the judicious use of detergents, without compromising assay performance.