Chemoenzymatic synthesis of selective multivalent neo-glycoproteins for galectin-4 inhibition

我们将制备用于选择性靶向半乳糖凝集素-4（Gal-4）的生物相容性新糖蛋白（NGP），并比较它们对人Gal-1和Gal-3的亲和力和选择性。选择性半乳糖凝集素抑制可应用于半乳糖凝集素相关病理学的治疗诊断学，例如心脏病、癌症发生或免疫病症。化学-酶促平台技术的使用，即聚糖表位和修饰的糖结构单元在天然样分支中的组装以及所获得的分支在蛋白质载体上的多价呈递将产生具有定制聚糖亲合力的新糖蛋白。我们将制备基于聚-N-乙酰乳糖胺的ABH血型抗原和硫酸化聚糖的文库以解决Gal-4的特异性结合，并且通过使用点击化学，我们将在二-O-炔丙基和四-O-炔丙基葡萄糖构建块和人血清白蛋白（HSA）新糖缀合物上产生聚糖分支。将使用ELISA和SPR研究Gal-4与单价聚糖和多价NGP的结合特性。将测定最佳候选物与表达Gal-4的细胞系的结合相互作用。

We will prepare biocompatible neo-glycoproteins (NGP) for selective targeting of galectin-4 (Gal-4) and compare their affinity and selectivity to human Gal-1 and Gal-3. Selective galectin inhibition may be applied in the theranostics of galectin-related pathologies, e.g. heart diseases, cancerogenesis or immune disorders. The use of chemo-enzymatic platform technologies, namely the assembly of glycan epitopes and modified sugar building blocks in nature-like branches and the multivalent presentation of obtained branches on a protein carrier will yield neo-glycoproteins with tailored glycan avidity. We will prepare a library of poly-N-acetyllactosamine-based ABH blood group antigens and sulfated glycans to address specific binding of Gal-4 and by using click chemistry we will create glycan branches on di-O-propargyl and tetra-O-propargyl glucose building blocks and human serum albumin (HSA) neoglycoconjugates. The binding properties of Gal-4 with monovalent glycans and multivalent NGP will be studied using ELISA and SPR. The best candidates will be assayed for binding interaction with Gal-4-expressing cell lines.