Preparation And Anti-Influenza Study Of Triazole-Linked Sialic Acid-Modified Polymaleic Acid Derivatives

Influenza is a contagious acute respiratory disease caused by influenza virus.Many pandemics around the world have caused a large number of morbidity and deaths,and also brought huge economic losses and social burdens to a country.At present,the first-line anti-influenza virus drugs used clinically,such as zanamivir,oseltamivir,peramivir,etc.,all bind to influenza virus neuraminidase（NA）competitively by simulating the structure of sialic acid,blocking the Influenza virus effluxes from host cells.However,in recent years,more and more influenza virus variants have become resistant to existing influenza virus inhibitors.Therefore,it is particularly important to develop new and effective influenza virus inhibitors.In this thesis,hemagglutinin（HA）and NA of influen za virus were used as targets,and sialic acid,the natural receptor of HA and NA,was used as raw material to design and synthesize triazole sialic acid-modified polymaleic acid derivatives（SA-PM）.In this work,monomeric sialic acid derivatives were designed and synthesized through chemical reactions such as the protection of sialic acid hydroxyl and carboxyl groups,sialic acid C-2chlorination,and azide substitution.The acid derivatives and the alkynyl-substituted small-molecule linking arms are linked in the manner of triazole,and the multivalent effect is used to cleverly link multiple monomeric sialic acid derivatives to the macromolecular backbone in a covalent manner.acid-linked to prepare triazole sialic acid-modified polymaleic acid（SA-PM）.The structure was verified by means of nuclear magnetic resonance and size exclusion chromatography,and it was found that each polymaleic acid backbone was connected to 134 monomeric sialic acid derivatives.The in vitro anti-influenza biological activity of the synthesized compounds was evaluated by hemagglutination inhibition assay（HAI）,neuraminidase inhibition assay（NAI）,cytopathic effect assay（CPE）and virus growth inhibition assay（VGI）.The results showed that the synthesized sialic acid-polymaleic acid polymer was obviously bound to the surface HA protein of influenza virus,and its anti-influenza virus IC50 reached 3.30,5.33,and 6.22μM,and its activity was nearly a thousand times higher than that of monomeric SA.,its 196.47 n M and 223.87 n M anti-influenza virus EC₅₀and cell viability in the cytopathic effect experiment results further indicate that the polymer has an inhibitory effect on influenza virus in tissue cells.At the same time,it also verified that the multivalent design of sialic acid-polymaleic acid covalent linkage is reasonable and effective,which provides a new idea for the design of multivalent influenza virus inhibitors.