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The Big Frontier of small molecules--RNA targeting
2024-03-07 15:49:45
It has long been thought that using chemicals to track RNA was futile because of its volatile properties. When scientists succeed, it is usually by accident.
In the past decade, for example, Merck has discovered an experimental antibiotic in development that blocks a type of bacterial RNA. Pfizer stumbled that its drug could affect the translation of a protein that regulates cholesterol.
Now, drug companies intend to do just that. With the help of better sequencing techniques, screening methods, and a broader understanding of RNA, researchers can more easily capture the appearance of information molecules and design drugs that attach to them. If successful, they could help achieve disease targets that small molecules cannot currently reach, providing new ways to treat neurodegenerative diseases, cancer and other conditions.
01 What are small molecules that target RNA?
They are the cornerstone of the pharmaceutical industry and make up the vast majority of drugs on the market. But the scope of small molecules is limited. Of the nearly 20,000 known genes, about 3,000 are considered consumable, meaning they can be targeted with drugs. Of the proteins they produce, only a few hundred are targets for existing drugs. Many other proteins don't have "pockets" where small molecules can embed, making them harder to reach.
Targeting RNA molecules that help make disease-associated proteins could give drugmakers another route. In theory, the drug could block the production of a potentially harmful protein or produce more beneficial proteins.
Another similar approach, used by Ionis Pharmaceuticals and other companies, uses strips of nucleic acid called antisense oligonucleotides to regulate or turn off the production of proteins. Both companies have advanced RNA research, particularly targeting drugs to treat rare genetic diseases such as spinal muscular atrophy and thyroid transamyloidosis, as well as more common conditions such as high cholesterol. The effects of the drug can last for months at a time.
While significant progress has been made in delivering these RNA therapies into the body, they are still largely limited to disease targets in the liver, meaning there is still a lot of disease that cannot be treated.
03 Small molecules targeting RNA are the next step.
The first to do so was Evrysdi, a drug jointly developed by Roche and PTC Therapeutics and approved in 2020 to help produce a protein that is lacking in patients with spinal muscular atrophy. An experimental Huntington's disease drug from Novartis called branaplam is also in human trials, but recent safety issues could hinder its progress.
So far, no startup developing small RNA-targeting molecules has taken a drug to clinical trials. But some companies' pipelines are beginning to take shape. Skyhawk appears to be on the eve of entering clinical trials, and the company has previously said it plans to begin moving its first drug into human trials sometime this year.