Exploring the structural and functional aspects of sialic acid mimetics

Abstract

Sialic acids Sia are nine carbon backbone monosaccharides typically found at the terminal position of the glycoproteins and glycolipids Over the decades sias have been reported in various pathological and physiological processes The invasion of virus bacteria also depends on specific sia patterns and aberrant sialylation is the feature of numerous of neurological immune cancer and congenital disorder of glycosylation Despite its widespread medical applications the structure function relation of the defined sialic acid sequence is still poorly understood In my thesis we describe the three distinct sialic acid modifications that independently generate crucial structural functional relation of sialic acid glycans The first target was to decipher the role of galactose as a penultimate sugar in sialic acid glycans We have synthesized Neu5Ac 945 2 6 Gal structural analogs and studies their binding to a series of Siglec The results showed distinct binding patterns with conserved Siglec hCD22 and mCD22 compared to rapid evolving Siglec Siglec 3 and 10 and constitute a valuable tool for designing Siglec specific molecules for therapeutic applications Furthermore these isostructural glycans were conjugated to KLH proteins and immunize the mice The immune response showed that mannose modification at the penultimate position of the sialic acid glycan induced high titer IgG antibody responses and these IgG antibodies showed efficient cross reactivity with native glycan Overall our results highlight a new potential approach to synthesize antigenic sugars to modulate immune responses Next we have synthesized sialic acid hydroxamate to understand the structural functional relation of the acidic group We found that biomimetic analogs possessed three distinct properties antioxidant nature metals chelating ability and Sia backbone to target AD Focusing on cytotoxicity caused by radicals and A 61538 metal complexes we demonstrated that hydroxamate ligand on sialic acid backbone protects the neural cells more efficiently