Keeping drugs on target

A method for identifying unintended effects of drugs is reported in the June issue of Nature Chemical Biology. During research and development, drugs are typically tested for their inhibition of a desired therapeutic target. However, when a drug is used clinically, side effects can be caused by unexpected interactions inside cells. These unintended effects may often be responsible for drug failure during clinical trials.

Stephen Michnick, John Westwick and colleagues have developed a high-throughput screen that monitors the effects of a drug on a wide range of cellular signaling pathways. They analyzed the effects of over 100 known drugs on these pathways and found that drugs with similar chemical structures or protein targets often had similar intended—and also unintended—effects on cellular signaling. Using this approach, they also showed that four known drugs also displayed previously unknown abilities to block the growth of cancer cells.

This new assay may now allow researchers to optimize the desired effects of drugs while simultaneously minimizing the undesired effects during the drug discovery process. Additionally, the ability to uncover unexpected but potentially useful drug actions, including inhibiting cell proliferation, could increase the efficiency of the drug discovery process.

Ion channels served up quickly

A new method for the rapid screening of membrane proteins, including ion channels, is reported in the June issue of Nature Chemical Biology. Despite the fact that only a small proportion of drugs target ion channels, these drugs yield multiple billions of dollars in sales each year. The search for new drugs targeting ion channels could lead to therapeutics in areas such as heart disease and cancer. However, identifying small-molecule inhibitors of ion channels has been slowed by the laborious process necessary to assay ion channel activity.

Holden and colleagues have now developed a rapid assay for screening membrane protein function. They first touch a glass probe to a colony of E. coli that is producing a membrane protein. They then touch this same glass probe to an artificial lipid bilayer that mimics the environment of a cellular membrane. By this simple transfer, which takes only minutes, a functional single channel can be tested for activity. As an example of the speed possible with this approach, the authors screened 100 pore-forming proteins, each with a different amino acid altered, and found a mutant of the pore protein with a new function in just a few hours.

In addition to its important potential to speed ion channel-targeted drug discovery, this method will likely also be useful for membrane protein proteomics and for developing new sensor technology.

Mothballs link cell death and cancer

Components of the humble mothball are carcinogens because they block cell suicide according to research in the June issue of Nature Chemical Biology.

Naphthalene and para-dichlorobenzene (PDCB) are carcinogenic compounds found in mothballs and air fresheners and are known environmental pollutants. In order to determine how these chemicals exert their carcinogenic effects, Xue and colleagues treated the microscopic worm, Caenorhabditis elegans with the compounds. In addition to causing a developmental delay and a reduced brood size, they inhibited caspases, the key enzymes that kick off the tidy self-destruction of cells.

Naphthalene and PDCB are the first small molecule inhibitors of programmed cell death in C. elegans and lend support to the idea that a decrease in cell death can lead to carcinogenesis.

Identifying off-target effects and hidden phenotypes of drugs in human cells

Marnie L MacDonald, Jane Lamerdin, Stephen Owens, Brigitte H Keon, Graham K Bilter, Zhidi Shang, Zhengping Huang, Helen Yu, Jennifer Dias, Tomoe Minami, Stephen W Michnick and John K Westwick

Published online: 07 May 2006 | doi 10.1038/nchembio790

Abstract | Full text | PDF | Supplementary information

Direct transfer of membrane proteins from bacteria to planar bilayers for rapid screening by single-channel recording

Matthew A Holden, Lakmal Jayasinghe, Oliver Daltrop, Amy Mason and Hagan Bayley

Published online: 07 May 2006 | doi 10.1038/nchembio793

Abstract | Full text | PDF | Supplementary information

The nongenotoxic carcinogens naphthalene and para-dichlorobenzene suppress apoptosis in Caenorhabditis elegans

David Kokel, Yehua Li, Jun Qin and Ding Xue

Published online: 14 May 2006 | doi 10.1038/nchembio791

Abstract | Full text | PDF | Supplementary information