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    Home > Biochemistry News > Biotechnology News > New progress in targeted protein degradation!

    New progress in targeted protein degradation!

    • Last Update: 2022-05-24
    • Source: Internet
    • Author: User
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    Targeted protein degradation is a hot area of ​​new drug development.
    It can be used to target previously "undruggable" targets and treat various diseases by degrading disease-related proteins

    .
    At present, a variety of targeted protein degradation technologies utilizing proteasome and lysosomal functions have been developed, including PROTAC protein degraders, molecular glues, LYTAC,

    etc.

    Autophagy is a way for cells to break down cytoplasmic components such as unwanted or harmful proteins and organelles
    .
    It engulfs cytoplasmic components that need to be broken down by autophagosomes and then transfers to lysosomes for degradation

    .
    A paper published recently in Nature Communications describes a technology for targeted protein degradation using autophagy

    .
    It can be used to degrade not only soluble oncogenic proteins, but also oligomers or protein deposits associated with neurodegenerative diseases

    .
    The researchers pointed out that this targeted protein degradation technology, named AUTOTAC, provides a new platform for new drug development and basic research

    .

    Previous studies have found that a receptor called p62 plays a key role in mediating targeted autophagy
    .
    It is activated by specific ubiquitin modifications on the surface of the target protein, and activated p62 mediates the production of autophagosomes, which engulf and transfer the target protein to lysosomes for degradation

    .
    Therefore, if a bispecific molecule is developed with one end capable of binding to the target protein and the other end capable of binding to the p62 receptor and activating them, it can lead to targeted autophagy against the target protein

    .

    ▲The mechanism of action of AUTOphagy-TArgeting Chimera (AUTOTAC) (Image source: Reference [1])

    Based on this concept, the researchers developed a variety of small-molecule compounds capable of activating p62 and tested their ability to degrade soluble proteins in vitro
    .
    The experimental results show that linking small-molecule compounds that directly activate p62 with molecules targeting the androgen receptor (AR) or estrogen receptor beta (ERβ) subunits can lead to the degradation of AR and ERβ through autophagy , and effectively inhibit the downstream signaling pathways they mediate

    .
    Androgen receptors and estrogen receptors are well-established drug targets in the treatment of prostate and breast cancer

    .
    Arvinas' original PROTAC protein degrader selected them as targets

    .

    In addition, the researchers examined the effect of the AUTOTAC technology on degrading aggregates composed of misfolded proteins
    .
    The authors point out in the paper that normally misfolded proteins can be degraded by the proteasome, however, misfolded proteins that form oligomers or larger protein deposits cannot enter the proteasome and therefore cannot be degraded by the proteasome

    .
    This makes autophagy the last line of defense against the deposition of pathogenic proteins

    .

    In this study, the scientists designed an AUTOTAC molecule that binds to a tau protein mutant, tauP301L, that readily forms neurofibrillary tangles
    .
    The experimental results show that AUTOTAC molecules can effectively remove the aggregates formed by tauP301L in vitro and in animal experiments

    .

    Previously, researchers have developed targeted protein degraders (called AUTACs) that stimulate autophagy by inducing specific ubiquitin modifications on the protein surface
    .
    The researchers noted that the AUTOTAC molecule directly activates p62, so it activates autophagy independent of ubiquitination of target proteins

    .
    This technique could provide a broad tool for protein degradation

    .

    References:

    [1] Ji et al.
    , (2022).
    The AUTOTAC chemical biology platform for targeted protein degradation via the autophagylysosome system.
    Nature Communications, https://doi.
    org/10.
    1038/s41467-022-28520-4

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