Department of Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, United States.
Department of Medicinal Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, United States.
Bioconjug Chem. 2022 Oct 19;33(10):1771-1784. doi: 10.1021/acs.bioconjchem.2c00226. Epub 2022 Aug 15.
The homeostasis of cellular activities is essential for the normal functioning of living organisms. Hence, the ability to regulate the fates of cells is of great significance for both fundamental chemical biology studies and therapeutic development. Despite the notable success of small-molecule drugs that normally act on cellular protein functions, current clinical challenges have highlighted the use of macromolecules to tune cell function for improved therapeutic outcomes. As a class of hybrid biomacromolecules gaining rapidly increasing attention, protein conjugates have exhibited great potential as versatile tools to manipulate cell function for therapeutic applications, including cancer treatment, tissue engineering, and regenerative medicine. Therefore, recent progress in the design and assembly of protein conjugates used to regulate cell function is discussed in this review. The protein conjugates covered here are classified into three different categories based on their mechanisms of action and relevant applications: (1) regulation of intercellular interactions; (2) intervention in intracellular biological pathways; (3) termination of cell proliferation. Within each genre, a variety of protein conjugate scaffolds are discussed, which contain a diverse array of grafted molecules, such as lipids, oligonucleotides, synthetic polymers, and small molecules, with an emphasis on their conjugation methodologies and potential biomedical applications. While the current generation of protein conjugates is focused largely on delivery, the next generation is expected to address issues of site-specific conjugation, stability, controllability, target selectivity, and biocompatibility.
细胞活动的动态平衡对于生物的正常运作至关重要。因此，调控细胞命运的能力对于基础化学生物学研究和治疗开发都具有重要意义。尽管小分子药物通常作用于细胞蛋白功能，并取得了显著的成功，但当前的临床挑战凸显了使用大分子来调节细胞功能以提高治疗效果的必要性。作为一类日益受到广泛关注的杂化生物大分子，蛋白质偶联物已显示出作为多功能工具来调控细胞功能以用于治疗应用（包括癌症治疗、组织工程和再生医学）的巨大潜力。因此，本文讨论了用于调控细胞功能的蛋白质偶联物的设计和组装的最新进展。此处涵盖的蛋白质偶联物根据其作用机制和相关应用分为三类：（1）调节细胞间相互作用；（2）干预细胞内生物途径；（3）终止细胞增殖。在每种类型中，都讨论了多种蛋白质偶联物支架，其中包含各种接枝分子，如脂质、寡核苷酸、合成聚合物和小分子，并重点介绍了它们的偶联方法和潜在的生物医学应用。虽然当前一代的蛋白质偶联物主要集中在递送方面，但下一代预计将解决定点偶联、稳定性、可控性、靶向选择性和生物相容性等问题。
