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    Home > Biochemistry News > Biotechnology News > How to design targeted protein degradation agents more effectively?

    How to design targeted protein degradation agents more effectively?

    • Last Update: 2022-01-12
    • Source: Internet
    • Author: User
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    Targeted protein degradation agents represented by PROTACs are one of the hotspots in the development of new drugs
    However, the factors that determine the specificity and activity of PROTACs are still not well understood

    In a paper published in Nature Communications recently, a research team led by Dr.
    Yaxia Yuan, Guangrong Zheng, and Daohong Zhou of the School of Pharmacy of the University of Florida found that when designing the PROTAC molecule, it was found on the target protein Lysine (Lys) with specific characteristics is very important

    Based on this strategy, the team developed a PROTAC degradation agent that simultaneously targets the degradation of BCL-xL and BCL-2

    Compared with the PROTAC molecule that only targets BCL-xL, it shows stronger anti-leukemia activity in in vitro experiments


    One end of the PROTAC molecule can bind to the target protein, and the other end can recruit E3 ubiquitin ligase to tag the target protein with ubiquitin to promote their degradation by the proteasome
    This mode of action may provide a new means of targeting past "undruggable" targets


    BCL-xL and BCL-2 are members of the anti-apoptotic BCL-2 protein family, which play an important role in promoting tumorigenesis, progression, and drug resistance
    Since many leukemias and solid tumors rely on both BCL-xL and BCL-2 to survive, the PROTAC molecules that simultaneously degrade them may have broader therapeutic potential


    The research team found that in the process of protein modification by ubiquitin, E3 ligase recruits E2 ligase and finally binds ubiquitin to lysine on the surface of the target protein
    Therefore, the surface of the target protein needs to have a lysine that can be reached by E2 ligase to connect the ubiquitin protein to it

    The number and conformation of these lysines have important effects on the activity and specificity of the protein degrading agent


    ▲The process of protein modification by ubiquitin (picture source: Rogerdodd, CC BY-SA 3.
    0 <http://creativecommons.
    0/>, via Wikimedia Commons)

    With the goal of improving the access of E2 ligase to lysine on the surface of the target protein, the researchers designed a series of innovative PROTAC molecules and discovered a PROTAC molecule that can simultaneously target and degrade BCL-xL and BCL-2
    In in vitro experiments, it showed stronger anti-leukemia activity compared with PROTAC molecules that only target the degradation of BCL-xL


    The researchers pointed out in the discussion section of the paper that whether the PROTAC molecule can successfully mediate the ubiquitin modification of the target protein not only needs to form a stable ternary structure with the E3 ligase and the target protein, but also whether there is a surface of the target protein that can be connected by E2 Enzyme access, the lysine linking the ubiquitin molecule is also crucial
    Therefore, computational model analysis of complexes including E2 ligase may help improve the specificity and activity of PROTAC molecules


    Reference materials:

    [1] Lv, et al.
    , (2021).
    Development of a BCL-xL and BCL-2 dual degrader with improved anti-leukemic activity, Nature Communications, https://doi.
    1038/s41467-021-27210 -x

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