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1.
Carbohydr Res ; 495: 108088, 2020 Sep.
Article in English | MEDLINE | ID: mdl-32807356

ABSTRACT

We report the preparation of multivalent amide-sialoside-decorated human serum albumin (HSA) and bovine serum albumin (BSA) as mimics of natural mucin and bioshields against influenza virus infection. Free sialic acid with an amine on C-2 was covalently attached to the protein scaffolds using di-(N-succinimidyl) adipate. Dynamic light scattering (DLS) showed that the synthetic neomucins were able to act as bioshields and aggregate the influenza virion particles. The dissociation constants (KD) of the interactions between the prepared glycoconjugates and three different viral strains were measured by isothermal titration calorimetry (ITC) indicating the multivalent presentation of sialyl ligands on the HSA and BSA backbones can dramatically enhance the adsorbent capability compared to the corresponding monomeric sialoside. Hemagglutinin inhibition (HAI) and neuraminidase inhibition (NAI) assays showed that the glycoconjugates acted as moderate HA and NA inhibitors, thus impeding viral infection. Moreover, the different binding affinities of the glycoproteins to HA and NA proteins from different influenza viruses demonstrated the importance of HA/NA balance in viral replication and evolution. These findings provide a foundation for the development of antiviral drugs and viral adsorbent materials based on mimicking the structure of mucin.


Subject(s)
Antiviral Agents/pharmacology , Glycerol/pharmacology , Influenza, Human/prevention & control , Mucins/metabolism , Orthomyxoviridae/drug effects , Stearates/pharmacology , Amides/chemistry , Amides/pharmacology , Animals , Antiviral Agents/chemistry , Cattle , Drug Combinations , Glycerol/chemistry , Hemagglutinin Glycoproteins, Influenza Virus/metabolism , Humans , Molecular Structure , Mucins/chemistry , Neuraminidase/antagonists & inhibitors , Neuraminidase/metabolism , Serum Albumin, Bovine/metabolism , Serum Albumin, Human/metabolism , Sialic Acids/chemistry , Sialic Acids/pharmacology , Stearates/chemistry
2.
Carbohydr Res ; 477: 32-38, 2019 May 15.
Article in English | MEDLINE | ID: mdl-30954773

ABSTRACT

A panel of divalent oseltamivir and guanidino oseltamivir analogues with esterification on the carboxyl acid group as potent inhibitors of influenza virus neuraminidase was prepared via click reaction. The primary structure activity relationship study demonstrated that appropriate distance between two oseltamivir monomers around 30 Šcan crosslink two adjacent neuraminidase tetramers on the virion surface and result in highly effective NA inhibitors against three strains of influenza virus and H7N9 virus like particle. This strategy also provides a basis for the multivalent modification on oseltamivir.


Subject(s)
Antiviral Agents/pharmacology , Neuraminidase/antagonists & inhibitors , Orthomyxoviridae/drug effects , Oseltamivir/pharmacology , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Dose-Response Relationship, Drug , Humans , Microbial Sensitivity Tests , Molecular Structure , Neuraminidase/metabolism , Orthomyxoviridae/enzymology , Oseltamivir/chemical synthesis , Oseltamivir/chemistry , Structure-Activity Relationship
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