Drug metabolism

MetaSite: understanding metabolism in human cytochromes from the perspective of the chemist. Cruciani, G. et al. J. Med. Chem. 48, 6970?6979 (2005)

During lead optimization, a major consideration of medicinal chemists is predicting the metabolism of the lead compound based on potential sites of degradation. A new computational tool called MetaSite has been developed by Cruciani et al. to make it easier for chemists to predict the possible positions at which a chemical could be metabolized and which cytochrome P450 isoforms are likely to be involved. The fully automated method can be used for all cytochrome P450 isoforms for which the three-dimensional structure is known, and should prove invaluable in drug and prodrug design.

HIV

From nonpeptide toward noncarbon protease inhibitors: metallacarboranes as specific and potent inhibitors of HIV protease. Cigler, P. et al. Proc. Acad. Natl Acad. Sci. 102, 15394?15399 (2005)

Currently used HIV pseudopeptide protease inhibitors have limited bioavailability and stability, and are expensive to manufacture. Cigler et al. have developed a group of inorganic icosa-hedral metallacarboranes that potently, specifically and selectively inhibit HIV protease. The most active compound showed promise in antiviral tests and caused no toxicity in tissue culture.

Cardiotoxicity

Phosphodiesterase 4D deficiency in the ryanodine-receptor complex promotes heart failure and arrhythmias. Lehnart, S. E. et al. Cell 123, 25?35 (2005)

Phosphodiesterase (PDE) inhibitors are being developed for several major diseases but have been associated with increased mortality from heart failure and arrhythmias in some clinical trials. Lehnart and colleagues show that knocking out the PDE4 gene in mice results in a phenotype that is more susceptible to progressive cardiomyopathy and arrhythmias. They established that PDE4D3 forms an essential part of the ryanodine-receptor (RyR2) complex required for excitation?contraction coupling in the heart, and that lack of PDE4D in mice results in a 'leaky' channel phenotype known to predispose individuals to heart failure.

Infectious diseases

Small-molecule inhibitor of Vibrio cholerae virulence and intestinal colonization. Hung, D.T. et al. Science 310, 670?674 (2005)

A novel approach to developing antibiotic agents is to target the genes involved in bacterial virulence. Hung et al. used this strategy to discover potential drugs for cholera. A high-throughput phenotypic screen was used to search for inhibitors of Vibrio cholerae virulence factor and identified a small-molecule inhibitor called virstatin. Virstatin prevents the expression of two essential virulence factors in V. cholerae and can protect infant mice from intestinal colonization by the pathogen.