RNA interference

Lack of interferon response in animals to naked siRNAs. Heidel, J. D. et al. Nature Biotech. 21 Nov 2004 (doi:10.1038/nbt1038)

Small interfering RNAs (siRNAs) are now widely used to silence specific target genes to elucidate their function and to aid in the identification of drug targets. These oligonucleotides also have potential as therapeutics, but one key concern is that they have the potential to elicit an interferon response. Heidel et al. show that it is possible to administer naked synthetic siRNAs to mice and downregulate an endogenous or exogenous target without inducing an interferon response.

Cardiovascular disease

Requirement of JNK2 for scavenger receptor A-mediated foam cell formation in atherogenesis. Ricci, R. et al. Science 306, 1558–1561 (2004)

The c-Jun N-terminal kinases (JNKs) have been implicated in pro-atherogenic processes. To clarify their role in these processes, Ricci et al. used mice that lacked apolipoprotein E (ApoE), which are prone to atherosclerosis, and which also lacked either JNK1 or JNK2. ApoE-deficient mice that lacked JNK2 developed significantly less atherosclerosis than either ApoE-deficient mice or ApoE-deficient mice that also lacked JNK1. Specific inhibition of JNK2 could therefore be a potential therapeutic approach to ameliorate atherosclerosis.

Anticancer drugs

Small molecule RITA binds to p53, blocks p53–HDM-2 interaction and activates p53 function in tumors. Issaeva, N. et al. Nature Med. 21 Nov 2004 (doi:10.1038/nm1146)

Inhibiting the interaction between the tumour suppressor p53 and HDM2, which leads to degradation of p53, is thought to have potential as a widely applicable and efficient anticancer strategy. However, discovering molecules that disrupt protein–protein interactions is challenging. Rather than searching for HDM2-binding molecules, Issaeva et al. screened for compounds that suppressed the growth of tumour cells in a p53-dependent manner, and identified a small molecule that inhibited the p53–HDM2 interaction — RITA — which had antitumour effects in mice.

Infectious disease

Combating drug-resistant bacteria: small molecule mimics of plasmid incompatibility as antiplasmid compounds. DeNap, J. C. B. et al. J. Am. Chem. Soc. 126, 15402–15404 (2004)

Many bacteria become resistant to antibiotics through the uptake of a plasmid that encodes resistance-mediating proteins. DeNap et al. identified a small molecule that can cause antibiotic-resistant bacteria to eliminate resistance-carrying plasmids (mimicking a natural mechanism known as plasmid incompatibility), which can resensitize bacteria to antibiotics, and which could therefore offer a novel strategy for combating antibiotic resistance.