Kinases

Screening for cell migration inhibitors via automated microscopy reveals a Rho-kinase inhibitor Yarrow, J. C. et al. Chem. Biol. 12, 385–395 (2005)

Cell migration is often studied using small molecules to perturb the complex underlying pathways, but a shortage of tool compounds led Yarrow et al. to develop a high-throughput image-based screen to identify inhibitors of this process. The screen is based on scratch-wound healing and measures decreased cell migration and aberrant morphology. A screen of 16,000 drug-like compounds identified subsets of different chemical classes that modulate cell migration. Secondary screening isolated 3-(4-pyridyl)indole (Rockout), a Rho-kinase (ROCK) inhibitor with comparable potency to the known ROCK inhibitor Y-27632.

Malaria

Crystal structure of the malaria vaccine candidate apical membrane antigen 1 Pizarro, J. C. et al. Science 308, 408–411 (2005)

Despite entering clinical trials as a malaria vaccine candidate, little is known about the structure or antigenicity of Plasmodium apical membrane antigen 1 (AMA1). Pizarro et al. provide the first crystal structure of the endoplasmic region of AMA1 from Plasmodium vivax and map an epitope within domain II that is recognized by an invasion-inhibitory monoclonal antibody specific for Plasmodium falciparum. Homology studies revealed a potential ligand-binding site within domain II that could be useful for drug design.

Immunotherapy

A chimeric human–cat fusion protein blocks cat-induced allergy Zhu, D. et al. Nature Med. 352, 777–785 (2005)

IgE-induced mediator release, which contributes to allergic rhinitis and asthma, can be blocked by aggregating the type II receptor for IgG (FcγRIIb) to the high-affinity IgE receptor FcεRI. Zhu et al. created a chimera (GFD) comprising human Fcγ and cat allergen Fel d1 that co-aggregates FcγRIIb with FcεRI-bound IgE, thereby blocking mediator release. GFD was shown to inhibit allergen-induced IgE-mediated mediator release in vitro from human basophils and mast cells, and in vivo in cat-allergen-sensitized mice.

Imaging

Noninvasive visualization of the activated αvβ3 integrin in cancer patients by positron emission tomography and [18F]galacto-RGD Haubner, R. et al. PLoS Med. 2, 244–252 (2005)

The integrin αvβ3 is a target for anti-angiogenic therapies and several clinical trials of αvβ3 antagonists are under way. Existing imaging technologies are limited in their capacity to monitor the effect of treatment. Haubner et al. have developed a radiolabelled αvβ3 antagonist, [18F]galacto-RGD, that was successfully used as a tracer for positron emission tomography (PET) to detect expression of αvβ3 in vitro and in vivo. Tracer uptake correlated with αvβ3 expression and was able to detect expression exclusively from tumour blood vessels. The study represents the first non-invasive assessment of αvβ3 expression in patients with malignant tumours.