Ghiselli Giancarlo
Independent Researcher, 1326 Spruce Street Suite 706, Philadephia, PA 19107, USA.
Medicines (Basel). 2019 Jul 29;6(3):80. doi: 10.3390/medicines6030080.
The polyanionic nature and the ability to interact with proteins with different affinities are properties of sulfated glycosaminoglycans (GAGs) that determine their biological function. In designing drugs affecting the interaction of proteins with GAGs the challenge has been to generate agents with high binding specificity. The example to emulated has been a heparin-derived pentasaccharide that binds to antithrombin-III with high affinity. However, the portability of this model to other biological situations is questioned on several accounts. Because of their structural flexibility, oligosaccharides with different sulfation and uronic acid conformation can display the same binding proficiency to different proteins and produce comparable biological effects. This circumstance represents a formidable obstacle to the design of drugs based on the heparin scaffold. The conceptual framework discussed in this article is that through a direct intervention on the heparin-binding functionality of proteins is possible to achieve a high degree of action specificity. This objective is currently pursued through two strategies. The first makes use of small molecules for which in the text we provide examples from past and present literature concerning angiogenic factors and enzymes. The second approach entails the mutagenesis of the GAG-binding site of proteins as a means to generate a new class of biologics of therapeutic interest.
硫酸化糖胺聚糖（GAGs）的多阴离子性质以及与不同亲和力蛋白质相互作用的能力决定了它们的生物学功能。在设计影响蛋白质与GAGs相互作用的药物时，面临的挑战是生成具有高结合特异性的药物。一直以来被模仿的例子是一种肝素衍生的五糖，它与抗凝血酶III具有高亲和力。然而，该模型在其他生物学情境中的适用性受到多方面质疑。由于其结构灵活性，具有不同硫酸化和糖醛酸构象的寡糖对不同蛋白质可表现出相同的结合能力并产生类似的生物学效应。这种情况给基于肝素支架设计药物带来了巨大障碍。本文讨论的概念框架是，通过直接干预蛋白质的肝素结合功能，可以实现高度的作用特异性。目前通过两种策略来实现这一目标。第一种策略利用小分子，本文从过去和现在的文献中提供了有关血管生成因子和酶的例子。第二种方法是对蛋白质的GAG结合位点进行诱变，以此生成一类具有治疗意义的新型生物制剂。
