Structure-based drug discovery by targeting N-glycan biosynthesis dolichyl-phosphate N-acetylglucosaminephosphotransferase

摘要

-Linked glycosylation is an evolutionarily conserved protein modification found across species, such as mammals, worms, insects, protozoa and certain types of fungi. Whereas, -linked glycosylation occurs in eukaryotes and widely in archaea, but very rarely in bacteria. Recent studies of cancer immunotherapy are based on immunogenicity of truncated -glycan antigens [ , ]. Despite the importance of -linked glycans for normal cells to develop tumor cells, immunotherapy that targets -linked glycans has not yet been developed mainly due to the lack of specificity of -linked glycans between normal and malignant cells. - or -glycan chains are synthesized by the sequential action of glycosyl transferases in the Golgi apparatus. It is a daunting task to discover drug-like inhibitors of glycosyl transferases that block the synthesis of specific branching processes in cancer cells, killing tumor cells selectively. It has long been known that -glycan biosynthesis can be inhibited by disruption of the first committed enzyme, DPAGT1 [ , ]. Selective DPAGT1 inhibitors have the promising therapeutic potential for certain solid cancers that require increased branching of -linked glycans in their growth progressions. Recently, two groups successfully co-crystalized DPAGT1 with UDP-GlcNAc or tunicamycin [ , ]. This structural information clarifies the binding domains of the enzymatic substrates and an inhibitor molecule, and provides valuable insight into a catalytic mechanism of DPAGT1, allowing us to design DPAGT1 inhibitors.