Institute of Molecular Medicine (IMM), Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai, 200120, China.
Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China.
Adv Sci (Weinh). 2024 May;11(17):e2308924. doi: 10.1002/advs.202308924. Epub 2024 Feb 29.
Selective protein degradation platforms have opened novel avenues in therapeutic development and biological inquiry. Antibody-based lysosome-targeting chimeras (LYTACs) have emerged as a promising technology that extends the scope of targeted protein degradation to extracellular targets. Aptamers offer an advantageous alternative owing to their potential for modification and manipulation toward a multivalent state. In this study, a chemically engineered platform of multivalent aptamer-based LYTACs (AptLYTACs) is established for the targeted degradation of either single or dual protein targets. Leveraging the biotin-streptavidin system as a molecular scaffold, this investigation reveals that trivalently mono-targeted AptLYTACs demonstrate optimum efficiency in degrading membrane proteins. The development of this multivalent AptLYTACs platform provides a principle of concept for mono-/dual-targets degradation, expanding the possibilities of targeted protein degradation.
选择性蛋白质降解平台在治疗开发和生物研究方面开辟了新途径。抗体结合的溶酶体靶向嵌合体(LYTAC)作为一种有前途的技术出现,将靶向蛋白质降解的范围扩展到细胞外靶标。适体由于其修饰和操纵为多价状态的潜力提供了有利的选择。在这项研究中,建立了基于多价适体的 LYTAC(AptLYTAC)的化学工程平台,用于靶向降解单个或双蛋白靶标。利用生物素-链霉亲和素系统作为分子支架,本研究表明,三价单靶向 AptLYTAC 在降解膜蛋白方面表现出最佳效率。这种多价 AptLYTAC 平台的开发为单/双靶标降解提供了一个概念原理,扩展了靶向蛋白质降解的可能性。