Antiviral drugs

An anti-CD45RO immunotoxin kills HIV-latently infected cells from individuals on HAART with little effect on CD8 memory. Saavedra-Lozano, J. et al. Proc. Natl Acad. Sci. USA 101, 2494–2499 (2004).

Although highly active antiretroviral therapy (HAART) can successfully control HIV infection for prolonged periods, reservoirs of latently infected T cells remain, representing a major obstacle to curing the disease. The authors tested an immunotoxin targeted to an antigen on latently infected T cells, and found that it could kill such cells from individuals receiving HAART, while sparing another type of T cell that is thought to have a key role in containing HIV infection.

Neurological disease

Cytosolic phospholipase A2 plays a key role in the pathogenesis of multiple sclerosis-like disease. Kalyvas, A. & David, S. Neuron 41, 323–335 (2004).

Experimental autoimmune encephalomyelitis (EAE) is an inflammatory, demyelinating disease that has been widely used as an animal model of multiple sclerosis (MS). Kalyvas and David provide evidence that cytosolic phospholipase A2 (cPLA2) is highly expressed in EAE lesions and show that inhibiting this enzyme with a small molecule markedly affects the onset and progression of EAE, suggesting that cPLA2 could be an attractive therapeutic target for MS.

Anticancer drugs

Small-molecule antagonists of the oncogenic Tcf/β-catenin protein complex. Lepourcelet, M. et al. Cancer Cell 5, 91–102 (2004).

Protein–protein interactions have traditionally been viewed as highly challenging drug targets, but significant progress has been made in this field recently, as highlighted by this paper. Lepourclet et al. developed a high-throughput assay for immuno-enzymatic detection of the interaction between β-catenin and the transcription factor Tcf4, which is important in colorectal cancer. Several diverse compounds that disrupt the Tcf4–β-catenin association were identified, and their activity confirmed in a range of independent assays.

Kinases

The structural basis for autoinhibition of FLT3 by the juxtamembrane domain. Griffith, J. et al. Mol. Cell 13, 169–178 (2004).

Mutations in the type III receptor tyrosine kinase (RTK) FLT3 that lead to its constitutive activation have been strongly implicated in acute myelogenous leukaemia. This paper presents the crystal structure of the inactive form of FLT3, which sheds light on how it could be activated by mutations, and which should aid in the design of drugs that target FLT3 and other type III RTKs.