• Study shows that RNA can be targeted by

    From ScienceDaily@1:317/3 to All on Wednesday, March 30, 2022 22:30:46
    Study shows that RNA can be targeted by small molecule drugs, creating
    new possibilities for disease treatment

    Date:
    March 30, 2022
    Source:
    Massachusetts General Hospital
    Summary:
    Until now, proteins have been the target of most medications for
    the prevention and treatment of human disease. Drug developers
    have perceived RNA to be too unstable to target with drug
    therapy. However, a screen of 50,000 compounds has revealed
    drug-like activity against an RNA prototype called Xist, a result
    that opens the door for development of new medications.



    FULL STORY ==========================================================================
    RNA (ribonucleic acid) plays many roles in human health, and now a study
    in the journal Nature offers powerful evidence that RNA could also be
    a viable target for drug development. This work, led by researchers
    at Massachusetts General Hospital (MGH), suggests that a new class of biological factors numbering in the thousands can be targeted and thereby heralds a new era in drug development.


    ========================================================================== Nearly all drugs currently available target one of approximately 700
    disease- related proteins among the roughly 20,000 human proteins
    identified by the Human Genome Project. However, in recent years there
    has been growing interest in expanding the list of "druggable" targets to include RNA. In cells, DNA (deoxyribonucleic acid) carries the genetic
    code for forming proteins. A segment of DNA is copied, or transcribed,
    into a "coding" RNA, which is in turn translated into protein. However,
    the vast majority of RNA in the human genome -- 98 percent -- is
    "noncoding." "These noncoding RNAs play very important roles in the
    genome, and we now understand that mutations in this noncoding space
    can result in disease," says the senior author of the Nature paper,
    Jeannie Lee, MD, PhD, of the Department of Molecular Biology at MGH. "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." However, the pharmaceutical industry has historically been hesitant to pursue RNA as a
    drug target. Proteins tend to have stable shapes, or conformations, which
    make them optimal targets: Drugs bind to proteins like a key in a lock.

    By contrast, explains Lee, RNA tends to be highly flexible, or "floppy,"
    and capable of assuming multiple conformations. "If a lock is constantly changing shape, your key is not going to work," says Lee. Noncoding
    RNA's unstable nature has made companies reluctant to invest in trying to develop medications that target it. However, it's known that some regions
    on RNA retain stable conformations, despite all of that shape-shifting,
    but finding such regions has been a challenge.

    Lee directs a molecular biology lab at MGH, where she and her team study
    RNA and its role in a biological process called X-chromosome inactivation (XCI), which deactivates one copy of the X chromosome in female mammals
    and is necessary for normal development. In a study led by postdoctoral
    fellow Rodrigo Aguilar, PhD, Lee's group collaborated with colleagues
    at Merck Research Laboratories to find out if RNA could be a viable drug target. The focus of the study was a form of noncoding RNA called Xist,
    which silences genes on the X chromosome. Finding a way to interfere
    with this process and reactivate a dormant X chromosome could help guide development of treatments for genetic disorders caused by mutations on
    the X chromosome (known as X-linked disorders), such as Rett syndrome
    and Fragile X syndrome.

    Together with Merck scientists Kerrie Spencer and Elliott Nickbarg,
    the MGH team screened Xist against a library of 50,000 small molecule
    compounds and found several that bind to a region called Repeat A (RepA)
    on Xist. One compound, which Lee's team named X1, had particularly
    interesting qualities: It prevented several key proteins, PRC2 and
    SPEN, from binding to RepA, which is necessary for Xist to silence the X chromosome. "As a result, X inactivation cannot take place," says Lee. To understand why, the team collaborated with structural biologists led
    by Trushar Patel of the University of Lethbridge in Canada. Normally,
    Xist's RepA can assume 16 different conformations, but X1 caused it to
    adopt a more uniform shape. This structural change prevented RepA from
    binding with PRC2 and SPEN.

    The approach employed in this study could be used to identify other
    RNA- targeting drugs. "This really opens up a large universe for new
    drug development," says Lee. "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."
    Lee is also a professor of Genetics at Harvard Medical School. Aguilar
    is now an assistant professor and researcher at Andres Bello University
    in Santiago, Chile.

    Funding for this work came from the Howard Hughes Medical Institute,
    the Pew Charitable Trust Latin American Fellows Program, and the MGH
    Fund for Medical Discovery.


    ========================================================================== Story Source: Materials provided by Massachusetts_General_Hospital. Note: Content may be edited for style and length.


    ========================================================================== Journal Reference:
    1. Rodrigo Aguilar, Kerrie B. Spencer, Barry Kesner, Noreen F. Rizvi,
    Maulik
    D. Badmalia, Tyler Mrozowich, Jonathan D. Mortison, Carlos Rivera,
    Graham F. Smith, Julja Burchard, Peter J. Dandliker, Trushar
    R. Patel, Elliott B. Nickbarg, Jeannie T. Lee. Targeting Xist with
    compounds that disrupt RNA structure and X inactivation. Nature,
    2022; DOI: 10.1038/s41586-022- 04537-z ==========================================================================

    Link to news story: https://www.sciencedaily.com/releases/2022/03/220330121240.htm

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