The structure-customized assembly of gangliosides derivatives via modular chemo-enzymatic cascade strategy reveal biological activities and identify drug ingredients

Abstract

Abstract Gangliosides play vital biological regulatory roles and are associated with neurological system diseases, malignancies, and immune deficiencies. They have received extensive attention in developing targeted drugs and diagnostic markers. However, it is difficult to obtain enough structurally defined gangliosides and derivatives especially at an industrial-relevant scale, which prevent exploring structure-activity relationships and identifying drug ingredients. Here, we report a highly modular chemo-enzymatic cascade assembly (MOCECA) strategy for customized and large-scale synthesis of ganglioside derivatives with various glycan and ceramide epitopes. We represently access several gangliosides with therapeutic promising and systematically prepared primary GM1 derivatives with diverse ceramides found in human brain. Through further process amplification, we achieved industrial production of ganglioside GM1 in the form of modular assembly at hectogram scale. Using MOCECA-synthesized GM1 derivatives, we found unique ceramide modifications on GM1 could enhance the ability to promote neurite outgrowth and cell viability. By comparing the structures with synthetic derivatives, we further resolved the contradicting descriptions of GM1 components in different pharmaceutical documents by reinterpreting the exact two-component structures of commercialized GM1 drugs. Because of its applicability and stability, the MOCECA strategy can be extended to prepare other glycosphingolipid structures, which may pave the way for developing new glycolipid drugs.