Interactions among biomacromolecules, predominantly noncovalent, underpin biological processes. However, recent advancements in biospecific chemistry have enabled the creation of specific covalent bonds between biomolecules, both in vitro and in vivo. This Review traces the evolution of biospecific chemistry in proteins, emphasizing the role of genetically encoded latent bioreactive amino acids. These amino acids react selectively with adjacent natural groups through proximity-enabled bioreactivity, enabling targeted covalent linkages. We explore various latent bioreactive amino acids designed to target different protein residues, ribonucleic acids, and carbohydrates. We then discuss how these novel covalent linkages can drive challenging protein properties and capture transient protein–protein and protein–RNA interactions in vivo. Additionally, we examine the application of covalent peptides as potential therapeutic agents and site-specific conjugates for native antibodies, highlighting their capacity to form stable linkages with target molecules. A significant focus is placed on proximity-enabled reactive therapeutics (PERx), a pioneering technology in covalent protein therapeutics. We detail its wide-ranging applications in immunotherapy, viral neutralization, and targeted radionuclide therapy. Finally, we present a perspective on the existing challenges within biospecific chemistry and discuss the potential avenues for future exploration and advancement in this rapidly evolving field.

中文翻译：

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生物大分子共价连接的生物特异性化学


生物大分子之间的相互作用（主要是非共价相互作用）支撑着生物过程。然而，生物特异性化学的最新进展使得能够在体外和体内生物分子之间创建特定的共价键。这篇综述追溯了蛋白质中生物特异性化学的演变，强调了基因编码的潜在生物反应性氨基酸的作用。这些氨基酸通过邻近的生物反应性选择性地与相邻的天然基团发生反应，从而实现靶向共价连接。我们探索了各种潜在的生物反应性氨基酸，旨在针对不同的蛋白质残基、核糖核酸和碳水化合物。然后我们讨论这些新颖的共价连接如何驱动具有挑战性的蛋白质特性并捕获体内短暂的蛋白质-蛋白质和蛋白质-RNA 相互作用。此外，我们还研究了共价肽作为潜在治疗剂和天然抗体位点特异性缀合物的应用，强调了它们与靶分子形成稳定连接的能力。重点关注邻近反应疗法 (PERx)，这是共价蛋白疗法的一项开创性技术。我们详细介绍了其在免疫治疗、病毒中和和靶向放射性核素治疗中的广泛应用。最后，我们对生物特异性化学中现有的挑战提出了看法，并讨论了这个快速发展的领域未来探索和进步的潜在途径。