Lead Discovery

Virtual screening to enrich hit lists from high-throughput screening: a case study on small-molecule inhibitors of angiogenin. Jenkins, J. L., Kao, R. Y & Shapiro, R. Proteins 50, 81–93 (2003)

Hit lists from high-throughput screening (HTS) often contain a large proportion of false positives, which means that follow-up assays are needed to find the truly active compounds. Consequently, there has been growing interest in integrating virtual screening (VS) with HTS with the aim of improving the quality of the hit-lists. Application of such a VS/HTS approach to the discovery of leads against the enzyme angiogenin leads to a sixfold enrichment in the hit rate compared with HTS alone.

Genomics

The protein kinase complement of the human genome. Manning, R. et al. Science 298, 1912–1934 (2002)

Using public and proprietary genomic, complementary DNA and expressed sequence tag sequences, the authors identify 518 putative protein kinases in the human genome, providing a starting point for comprehensive analysis of protein phosphorylation in normal and disease states.

Hormone Receptors

Rapid nontranscriptional activation of endothelial nitric oxide synthase mediates increased cerebral blood flow and stroke protection by corticosteroids. Limbourg, F. P. et al. J. Clin. Invest. 110, 1729–1738 (2002)

Classically, steroids hormones act by modulating gene expression, with effects occuring over hours to days. However, growing evidence indicates that important effects of steroids are mediated through rapid nontranscriptional mechanisms. Limbourg et al. show that the neuroprotective effects of corticosteroids are mediated through rapid non-nuclear activity of the glucocorticoid receptor (GR), suggesting that drugs that selectively activate the nontranscriptional actions of GR might be beneficial in stroke.

Gene Therapy

Inhibiting HIV-1 infection in human T cells by lentiviral-mediated delivery of small interfering RNA against CCR5. Qin, X. -F. et al. Proc. Natl Acad. Sci. USA 100, 183–188 (2003)

The use of small interfering RNA (siRNA) to reduce expression of specific genes has great therapeutic potential, but a key challenge is delivering siRNA into the target cells. By using a lentiviral vector derived from HIV-1, Qin et al. introduced siRNA against the chemokine receptor CCR5 — a necessary co-receptor for infection by HIV-1 — into T cells, which led to up to 10-fold reduction in CCR5 expression, and a 3–7 fold reduction in the number of T cells infected after challenge with HIV-1.