It takes more than the right genes for good health. Those genes must also be switched on at the right times; if they're not, that can trigger diseases from cancer to diabetes. Now, chemists have made small druglike molecules to serve as switches, something only proteins and other biomolecules could manage until now.
In the body, an activator protein typically does its job in two steps: One "arm" binds to its genetic targets, and another arm grabs onto other proteins that turn on the gene--a process called transcription activation. Smaller biomolecules, such as RNA snippets and protein fragments called peptides, can also work as activators. But these compounds can break down quickly and have other drawbacks.
To get around this problem, chemist Anna Mapp of the University of Michigan, Ann Arbor, and her colleagues started by scrutinizing peptides known to activate particular genes. Although the peptides had different structures, they typically shared a handful of chemical features, such as phyenyl, hydroxyl, carboxylic acid, and isobutyl groups.
The same groups are found in a family of ring-containing compounds, known as isoxazolidines, which are longer-lived than peptides. So Mapp and her graduate students Aaron Minter and Brian Brennan synthesized several versions. Then they grafted on gene-seeking "arms," fastening each molecule to a protein known to target the DNA in a well-known engineered gene. To test their molecules, the researchers added an extract made from the nuclei of human cells to test tubes containing the modified isoxazolidine molecules. They measured an uptick in messenger RNA from the target gene, they report in the advance online publication of the Journal of the American Chemical Society. That increase was a sign that the small molecules had switched on gene transcription.
"It's really exciting that they have small molecules that can mimic natural activators," says Aseem Ansari, a biochemist at the University of Wisconsin, Madison. Ansari hopes the new molecules might eventually serve as scaffolds for a new family of gene-controlling drugs.