31 March 2022

The target is non–coding RNAs

Study: RNA can also become a target for drugs

Tatiana Matveeva, "Scientific Russia"

According to a new study conducted at the Massachusetts General Hospital (MGH, USA), low-molecular-weight drugs can affect RNA, which opens up new opportunities for the treatment of diseases, the press service of MGH reports. The results of the work appeared in the journal Nature (Aguilar et al., Targeting Xist with compounds that disrupt RNA structure and X inactivation).

Almost all drugs currently available target one of the approximately 700 proteins associated with the disease – among the approximately 20,000 proteins identified as part of the Human Genome project. However, in recent years there has been a growing interest in expanding the list of "medicinal" targets by including RNA. In cells, DNA carries the genetic code for the formation of proteins. The DNA segment is copied or transcribed into "coding" RNA, which, in turn, is translated into protein. However, the vast majority of RNAs in the human genome are "non-coding".

"These non–coding RNAs play a very important role in the genome, and now we understand that mutations in this non-coding space can lead to disease," the senior author of the article notes Ginny Lee, MD, is a member of the Department of Molecular Biology at MGH. – And there may be many more of these RNA genes than there are protein-coding genes. If we could target these RNAs, we would greatly expand the universe in which we can find drugs to treat patients."

Proteins, as a rule, have a stable shape or conformation, which makes them optimal targets: drugs bind to proteins according to the "key–lock" principle. RNA is more "flexible" and can take several conformations: if the lock is constantly changing shape, the key is unlikely to fit. Nevertheless, some RNA sites retain stable conformations despite shape changes, but it is not easy to find such sites.

In this work, the researchers focused on a form of non-coding RNA called Xist, which suppresses genes on the X chromosome. Out of 50 thousand low molecular weight compounds, scientists have identified several that bind to the region on Xist – Repeat A (RepA). One compound, called X1, had particularly interesting properties: it prevented the binding of several key proteins, PRC2 and SPEN, to RepA, which is necessary for Xist to silence the X chromosome. Normally RepA Xist can take 16 different conformations, but X1 forced it to take a more uniform shape. This structural change prevented RepA from binding to PRC2 and SPEN.

Scientists will be able to apply the approach used in this study to identify other drugs targeting RNA.

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