What if a drug target and a drug synthesis site were one and the same? Such a biochemical twofer would essentially turn a diseased cell into a reaction vessel. A neat trick, to be sure. More important it would, potentially, evade an all-too-familiar problem—the tradeoff between low molecular weight therapeutics (which offer higher permeability) and high molecular weight therapeutics (which offer higher potency).

Deploying the curious term “in cellulo,” researchers at The Scripps Research Institute report that they have used a chemical approach to turn diseased cells into unique manufacturing sites for molecules that can treat a form of muscular dystrophy. The chemical approach, a form of click chemistry, allowed the researchers to transform small molecules into potent, multivalent ligands by a reaction that was catalyzed by the very RNA defect that caused the disease.

The researchers published their findings August 27 in the journal Angewandte Chemie, in an article entitled, “A Toxic RNA Catalyzes the In Cellulo Synthesis of Its Own Inhibitor.”

“Small molecule modules with precisely positioned alkyne and azide moieties bind adjacent internal loops in r(CCUG)exp, the causative agent of myotonic dystrophy type 2 (DM2),” wrote the authors, who added that the small modules were “transformed into oligomeric, potent inhibitors of DM2 RNA dysfunction by a Huisgen 1,3-dipolar cycloaddition reaction.”

This reaction, the researchers noted, is a variant of click chemistry, a process invented by Nobel laureate K. Barry Sharpless, a chemist at TSRI, to quickly produce substances by attaching small units or modules together in much the same way this occurs naturally. “In my opinion,” said TSRI professor and study leader Matthew Disney, Ph.D., “this is one unique and a nearly ideal application of the process Sharpless and his colleagues first developed.”

“Because the treatment is synthesized only in diseased cells, the compounds could provide highly specific therapeutics that only act when a disease is present,” Dr. Disney continued. “This means we can potentially treat a host of conditions in a very selective and precise manner in totally unprecedented ways.”

In the current study, the inhibitory assembly turned out to be 1,000 times more potent than the modular, small molecule precursors and 100 times more potent than the research team’s most active lead compound. The study, according to research associate Suzanne Rzuczek, Ph.D., marked the first time such an approach was validated in live cells.

Given the predictability of the process and the nearly endless combinations, translating such an approach to cellular systems could be enormously productive, Disney explained. RNAs make ideal targets because they are modular, just like the compounds for which they provide a molecular template.

Not only that, he added, but many similar RNAs cause a host of incurable diseases such as ALS (Lou Gehrig's Disease), Huntington's disease, and more than 20 others for which there are no known cures, making this approach a potential route to develop lead therapeutics to this large class of debilitating diseases.

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