如噬菌体展示技术在筛选肽和蛋白质组合文库中的广泛应用不仅促进了新的重组抗体的产生,而且还显著富集了具有与免疫球蛋白没有同源性的多肽支架的蛋白质结合剂。这些创新的合成结合蛋白(SBP)平台的数量已经增长,现在包括单体/adnectin,DARPins,脂质运载蛋白/抗钙素,以及各种微小蛋白,如亲和体和结结蛋白,在其他人中。它们是开发复杂亲和力工具的通用模块,在诊断和治疗环境中都有希望。最佳支架通常具有低分子量,最小的免疫原性,并表现出对各种挑战性条件的抵抗力,包括蛋白水解-使其可能适合口服给药。在减少细胞内环境下保留功能也是有利的。然而,其功能最重要的是支架耐受多个位置的突变的能力,允许形成足够大的靶结合区。这是通过图书馆建设来实现的,筛选,以及在适当系统中的后续表达式。具有高热力学稳定性的支架尤其受到新SBP开发者的垂涎。这些正在稳步进入临床环境,特别是在信号通路中作为癌蛋白的拮抗剂。这篇综述调查了SBP的多样化景观,特别强调靶向癌蛋白KRAS的抑制剂,并强调了SBP在肿瘤学领域的开创性机会。
Extensive application of technologies like phage display in screening peptide and protein combinatorial libraries has not only facilitated creation of new recombinant antibodies but has also significantly enriched repertoire of the protein binders that have polypeptide scaffolds without homology to immunoglobulins. These innovative synthetic binding protein (SBP) platforms have grown in number and now encompass
monobodies/adnectins, DARPins, lipocalins/anticalins, and a variety of miniproteins such as affibodies and knottins, among others. They serve as versatile modules for developing complex affinity tools that hold promise in both diagnostic and therapeutic settings. An optimal scaffold typically has low molecular weight, minimal immunogenicity, and demonstrates resistance against various challenging conditions, including proteolysis - making it potentially suitable for peroral administration. Retaining functionality under reducing intracellular milieu is also advantageous. However, paramount to its functionality is the scaffold\'s ability to tolerate mutations across numerous positions, allowing for the formation of a sufficiently large target binding region. This is achieved through the library construction, screening, and subsequent expression in an appropriate system. Scaffolds that exhibit high thermodynamic stability are especially coveted by the developers of new SBPs. These are steadily making their way into clinical settings, notably as antagonists of oncoproteins in signaling pathways. This review surveys the diverse landscape of SBPs, placing particular emphasis on the inhibitors targeting the oncoprotein KRAS, and highlights groundbreaking opportunities for SBPs in oncology.