In Brief

Lead identification

Pyridopyrimidine derivatives as inhibitors of cyclic nucleotide synthesis: application for treatment of diarrhea. Kots, A. Y. et al. Proc. Natl Acad. Sci. USA 105, 8440–8445 (2008)

Acute secretory diarrhoea induced by Escherichia coli infection involves binding of stable toxin to guanylyl cyclase C (GC-C; also known as GUCY2C). Kots and colleagues identified BPIPP as an inhibitor of GC-C. The compound inhibited chloride-ion transport stimulated by activation of guanylyl cyclases in vitro, and suppressed stable toxin-induced fluid accumulation in an in vivo rabbit intestinal loop model. So, BPIPP may be a promising lead compound for the treatment of diarrhoea and other conditions involving cyclic nucleotide disturbances.

G-protein-coupled receptors

Structure of a β₁-adrenergic G-protein-coupled receptor. Warne, T. et al. Nature 25 June 2008 (doi: 10.1038/nature07101)

The recent elucidation of the crystal structure of the β₂-adrenergic receptor (AR) raised questions about the structural basis of subtype specificity of β-AR ligands. Warne and colleagues report the 2.7Å resolution crystal structure of a turkey β₁-AR in complex with a high-affinity antagonist. Binding of antagonists to β₂-AR and β₁-AR involve similar interactions. However, a short helix in cytoplasmic loop 2 — not observed in rhodopsin or β₂-AR — directly interacts with the highly conserved DRY motif at the end of helix 3 by means of a tyrosine, which is essential for receptor activation.

Parasite infection

Immunity to a salivary protein of a sand fly vector protects against the fatal outcome of visceral leishmaniasis in a hamster model. Gomes, R. et al. Proc. Natl Acad. Sci. USA 105, 7845–7850 (2008)

Visceral leishmaniasis — transmitted by sandflies — is a fatal disease for which no vaccine is currently available. Gomes and colleagues developed a hamster model of the disease that mimics its natural progression. In this model, immunization with 16 DNA plasmids coding for sandfly salivary proteins resulted in the identification of LJM19, a novel 11 kDa protein. Hamsters immunized with LJM19 were protected against the fatal outcome of visceral leishmaniasis, and mounted a delayed-type hypersensitivity immune response. This highlights the feasibility of using arthropod saliva as a strategy against vector-borne diseases.

Antibody-mediated diseases

The proteasome inhibitor bortezomib depletes plasma cells and protects mice with lupus-like disease from nephritis. Neubert, K. et al. Nature Med. 14, 748–755 (2008)

Autoantibody-mediated diseases — such as systemic lupus erythematosus — are difficult to treat because long-lived plasma cells that produce autoantibodies resist current and experimental approaches. Neubert and colleagues show that the approved proteasome inhibitor bortezomib depletes short-lived and long-lived plasma cells, mainly as a result of activation of the terminal unfolded protein response. Treatment of mice with lupus-like disease with bortezomib decreased dsDNA-specific antibody production, proteinuria and kidney damage, and considerably prolonged survival.