Messenger RNA (mRNA) is the Aide-de-Camp of the cell. It carries a design code—the gene—from General DNA to the ribosome. The ribosome is charged with carrying out the orders by translating that code into a particular protein. If there is a defect in the DNA, that defect will be translated to the mRNA, which can either wreak havoc itself or pass the task on to the protein.
From anti-cancer medications to your favorite over-the-counter headache remedy, most modern pharmaceuticals are small molecules that target some defective or overactive protein that is produced by your cells.* But, another way to treat a genetic disease might be to try to stop the malfunctioning mRNA, either by impeding its progress or by cutting out the defect before it can cause any problems.
In a communication published in December in Angewandte Chemie International Edition, a group of chemists at the Scripps Research Institute in Florida report a new, potentially general, strategy for cutting out an unwanted piece of mRNA using a small molecule. While other molecules that can cleave RNA have been reported before, this is the first time that this has been done in living cells.
Building on research reported in February 2012, the scientists, lead by Professor Matthew Disney, have designed a small molecule that will attach specifically to a superfluous and destructive section of mRNA that causes many of the symptoms of myotonic dystrophy—a degenerative muscle disease. This pernicious piece of RNA captures proteins that are necessary for heart function, insulin sensitivity, and muscle relaxation, among others.
The molecule described in this report is loaded with a “hydroxyl-radical-producing warhead”, which, when activated by ultraviolet light, will release an oxygen free radical that destroys some of the unwanted section of RNA. The chemists also show that this cleavage can happen in HeLa cells** containing the defective mRNA without damaging the cells. This frees some of the captured protein, although more remains trapped than would be in a completely healthy cell.
This line of defense is still a long way off from use in the clinic. Nevertheless, it does provide an intriguing proof-of-concept, and could one day lead to next generation technologies for fighting many diseases that are caused by a rogue gene.
Also see: J.L. Childs-Disney, J. Hoskins, S.G. Rzuczek, C.A. Thornton, and M.D. Disney, “Rationally Designed Small Molecules Targeting the RNA That Causes Myotonic Dystrophy Type 1 Are Potently Bioactive”, ACS Chem. Bio., 2012, 7, 856−862, doi: 10.1021/cb200408a
*A notable exception is antibiotics, which are also small molecules, but which I exclude because they act on bacteria instead of on your cells.
**HeLa Cells are a human cell line derived from the cervical cancer of a woman named Henrietta Lacks.
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