Ion Channels

Crystal structure of a bacterial homologue of Na+/Cl−-dependent neurotransmitter transporters. Yamashita, A. et al. Nature 437, 215–223 (2005)

Na+/Cl−-dependent neurotransmitter transporters are drug targets for a variety of neurological disorders, but there is no currently no crystal structure to aid further drug discovery efforts. This paper reports the crystal structure of a leucine-bound bacterial homologue, LeuTAa, which will help to define the residues and domains that form the extracellular and intracellular gates of this transporter class.

Gene Therapy

In vitro -generated regulatory T cells induced by Foxp3-retrovirus infection control murine contact allergy and systemic autoimmunity. Loser, K. et al. Gene Ther. 12, 1294–1304 (2005)

Impaired suppressor function of regulatory CD4+CD25+ T cells is implicated in many autoimmune diseases, but efforts to use regulatory T cells to treat these disorders have been hindered by the poor availability of this T cell subtype. Loser et al. generated regulatory T cells in vitro by infecting naive T cells with a retrovirus encoding Foxp3, a transcription factor involved in the development of CD4+CD25+T cells. Injection of Foxp3-infected cells inhibited contact hypersensitivity and prevented the ongoing development of autoimmune dermatitis in sensitized mice.

Infectious Disease

Inhibitors of cathepsin L prevent severe acute respiratory syndrome coronavirus entry. Simmons, G. et al. Proc. Natl Acad. Sci. USA 102, 11876–11881 (2005)

Infection by the coronavirus that causes severe acute respiratory syndrome (SARS-CoV) has been shown to be sensitive to endosomal pH perturbations. Simmons et al. searched for pH-dependent endosomal proteins that might be involved in infectivity and found that specific inhibitors of cathepsin L block SARS-CoV infection of cells in culture. Infection was shown to involve three steps: receptor binding, conformational change of the viral spike glycoprotein, and subsequent cathepsin L-mediated proteolysis within endosomes. Inhibitors that target cathepsin L could be beneficial as anti-infective drugs against SARS.

Anticancer Drugs

Pleiotropic effects of HIF-1 blockade on tumor radiosensitivity. Moeller, B. J. et al. Cancer Cell 8, 99–110 (2005)

Activation of hypoxia-inducible factor-1 (HIF1) can cause resistance to radiotherapy in tumours and it is proposed that HIF1 inhibitors could be used sensitize tumours to radiation. This paper reports on the complexity of HIF1 signalling under various tumour conditions and reveals that HIF1 radiosensitizes tumours by promoting radiation-induced p53 activation, ATP metabolism and proliferation, yet causes radioresistance by stimulating endothelial cell survival. The success of HIF1 inhibitors as a complement to radiotherapy will therefore depend on the 'sequencing' of treatment.