Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94143, United States.
Cardiovascular Research Institute, University of California, San Francisco, California 94143, United States.
J Am Chem Soc. 2021 Jan 20;143(2):593-598. doi: 10.1021/jacs.0c10008. Epub 2021 Jan 4.
Targeted protein degradation has emerged as a new paradigm to manipulate cellular proteostasis. Proteolysis-targeting chimeras (PROTACs) are bifunctional small molecules that recruit an E3 ligase to a target protein of interest, promoting its ubiquitination and subsequent degradation. Here, we report the development of antibody-based PROTACs (AbTACs), fully recombinant bispecific antibodies that recruit membrane-bound E3 ligases for the degradation of cell-surface proteins. We show that an AbTAC can induce the lysosomal degradation of programmed death-ligand 1 by recruitment of the membrane-bound E3 ligase RNF43. AbTACs represent a new archetype within the PROTAC field to target cell-surface proteins with fully recombinant biological molecules.
靶向蛋白降解已成为一种新的范例，可以用于操纵细胞蛋白质稳态。蛋白水解靶向嵌合体（PROTACs）是双功能小分子，可招募 E3 连接酶到感兴趣的靶蛋白上，促进其泛素化和随后的降解。在这里，我们报告了基于抗体的 PROTACs（AbTACs）的开发，这是完全重组的双特异性抗体，可招募膜结合 E3 连接酶以降解细胞表面蛋白。我们表明，AbTAC 可以通过募集膜结合 E3 连接酶 RNF43 诱导程序性死亡配体 1 的溶酶体降解。AbTAC 代表 PROTAC 领域中的一个新范例，可使用完全重组的生物分子靶向细胞表面蛋白。
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