RNA targeted by small molecule drugs, likely to create new pathways for disease treatment

RNA (ribonucleic acid) is involved in many aspects of human health, and a new study published in the journal Nature provides compelling evidence that RNA could be a promising pharmacological target.

This study, conducted by Massachusetts General Hospital (MGH) scientists, reveals that a new class of biological variables with tens of thousands of members can be targeted, ushering in a new era in medication development.

Among the over 20,000 human proteins identified by the Human Genome Project, almost all currently available medications target one of the 700 disease-related proteins approximately. Furthermore, there has been an increasing interest in including RNA in the list of “druggable” targets in recent times.

The genetic code for creating proteins is carried by DNA (deoxyribonucleic acid) in cells. A piece of DNA is copied into a “coding” RNA, which is then translated into protein. The great majority of RNA in the human genome, therefore, is “noncoding,” accounting for 98%.

These noncoding RNAs play very important roles in the genome, and we now understand that mutations in this noncoding space can result in disease. And there may be far more of these RNA genes than there are protein-coding genes. If we could target these RNAs, we would hugely increase the universe in which we can find drugs to treat patients.”

Jeannie Lee, MD, PhD, Study Senior Author, Department of Molecular Biology, Massachusetts General Hospital

The pharmaceutical industry, on the other hand, has been reticent to approach RNA as a medication target in the past. Proteins have very stable forms, or conformations, making them ideal targets: Drugs bind to proteins in the same way as a key binds to a lock. RNA, on the other hand, is very flexible, or “floppy,” and capable to take various conformations, according to Lee.

If a lock is constantly changing shape, your key is not going to work.”

Jeannie Lee, MD, PhD, Study Senior Author, Department of Molecular Biology, Massachusetts General Hospital

Due to the obvious instability of noncoding RNA, drug industry has been hesitant to invest in developing drugs that target it. Despite all of this shape-shifting, some areas of RNA are known to maintain stable conformations, but locating these regions has proven difficult.

Lee leads a molecular biology lab at MGH, where she and her colleagues research RNA and its function in X-chromosome inactivation (XCI), and a biological process that disables one copy of the X chromosome in female mammals and is required for normal evolution.

Lee’s group cooperated with colleagues at Merck Research Laboratories in a study led by postdoctoral fellow Rodrigo Aguilar, PhD, to see if RNA could be a feasible therapeutic target. The study focused on Xist, a type of noncoding RNA that silences genes on the X chromosome.

Finding a technique to disrupt this mechanism and revive an inactive X chromosome could allow the development of treatments for X-linked illnesses like Rett syndrome and Fragile X syndrome, which are caused by abnormalities on the X chromosome.

The MGH researchers evaluated Xist against a library of 50,000 small molecule compounds with Merck scientists Kerrie Spencer and Elliott Nickbarg, and discovered many that bind to a location on Xist termed repeat A (RepA).

One compound, called X1 by Lee’s team, exhibited particularly intriguing properties: PRC2 and SPEN, two crucial proteins, were unable to connect to RepA, which is required for Xist to mute the X chromosome.

“As a result, X inactivation cannot take place,” says Lee. The team worked with structural biologists led by Trushar Patel of the University of Lethbridge in Canada to figure out why. Xist’s RepA can typically adopt 16 various conformations, but X1 induced it to take on a more consistent shape. RepA was unable to bind to PRC2 and SPEN as a result of this structural alteration.

The method applied in this research could be used to discover other RNA-targeting medicines.

This really opens up a large universe for new drug development. Now we don’t just have 700 proteins to target using small molecules. In the future, we may have tens and possibly hundreds of thousands of RNAs to target to cure disease.”

Jeannie Lee, MD, PhD, Study Senior Author, Department of Molecular Biology, Massachusetts General Hospital

Lee is also a Harvard Medical School professor of genetics. In Santiago, Chile, Aguilar is presently an assistant professor and scientist at Andres Bello University.