Gene Therapy

Synthetic small inhibiting RNAs: Efficient tools to inactivate oncogenic mutations and restore p53 pathways. Martinez, L. A. et al. Proc. Natl Acad. Sci. USA 99, 14849–14854 (2002)

RNA interference — a highly selective gene silencing mechanism involving small inhibiting RNAs (siRNAs) that bind to and degrade specific messenger RNAs — is causing much excitement in drug discovery at present. One potential application is with the tumour-suppressor gene p53, as this is inactivated by single-base-pair mutations in more than 50% of all cases of cancer. The authors found that a single base difference in siRNAs distinguished between mutant and wild-type p53 that were co-expressed in cells, and restored wild-type p53 function. The findings show that siRNA could be used to selectively inhibit oncogenes, and could therefore potentially form the basis of a customized gene-targeted cancer treatment.

Lead Identification

Identification of potent and selective small-molecule inhibitors of caspase-3 through the use of extended tethering and structure-based drug design. Choong, I. C. et al. J. Med. Chem. 45, 5005–5022 (2002)

Caspases are important in inflammation and apoptosis, and potent and selective caspase inhibitors would be useful in the delineation of the roles of individual caspases, and as leads for drug discovery. However, most inhibitors discovered so far are not completely specific, and are often peptidic, limiting their potential as drug leads. By using an initial hit discovered from a novel 'extended tethering' strategy, in which a fragment that is known to bind to the target is covalently attached to the active site and then allowed to react reversibly with a library of compounds to probe the characteristics of the binding site, Choong and colleagues designed several potent and selective non-peptidic inhibitors of caspase-3.

Structure-Based Drug Design

NMR-based modification of matrix metalloproteinase inhibitors with improved bioavailability. Hadjuk, P. J. et al. J. Med. Chem. 2002 Nov 20 (doi: 10.1021/jm020160g)

Automated analysis of large sets of heteronuclear correlation spectra in NMR-based drug discovery. Damberg, C. S. et al. J. Med. Chem. 2002 Nov 14 (doi: 10.1021/jm020866a)

NMR (nuclear magnetic resonance) spectroscopy has evolved into an important technique in support of structure-based drug design (see Wüthrich et al. Nature Rev. Drug Disc. 1, 211–219 (2002)). Hadjuk et al. show that NMR-based screening of fragments can be effectively applied to improve the physiochemical or pharmacokinetic profile of lead compounds, and Damberg et al. describe an automated procedure for the analysis of the many spectra that such strategies typically require.