The Natural Oligoribonucleotides Functionalized by D-Mannitol Affected Interactions of Hemagglutinin with Glycan Receptor Indicating Anti-Influenza Activity.

Zenoviy Tkachuk,Roman O Nikolaiev,Igor Zhukov,Kosma Szutkowski,Nataliia Melnichuk

doi:10.3390/membranes11100757

Abstract

Hemagglutinin (HA), the class I influenza A virus protein is responsible for the attachment of virus particles to the cell by binding to glycan receptors, subsequent virion internalization, and cell entry. Consequently, the importance of HA makes it a primary target for the development of anti-influenza drugs. The natural oligoribonucleotides (ORNs) as well as their derivatives functionalized with D-mannitol (ORNs-D-M) possess anti-influenza properties in vitro and in vivo due to interaction with HA receptor sites. This activity suppresses the viral infection in host cells. In the present work, the complexes of ORNs and ORNs-D-M with HA protein were studied by agglutination assay, fluorescence spectroscopy, as well as molecular docking simulations. Acquired experimental data exhibited a decrease in HA titer by 32 times after incubation with the ORNs-D-M for 0.5–24 h. Quenching fluorescence intensity of the HA suggests that titration by ORNs and ORNs-D-M probably leads to changes in the HA structure. Detailed structural data were obtained with the molecular docking simulations performed for ORNs and ORNs-D-M ligands containing three and six oligoribonucleotides. The results reveal that a majority of the ORNs and ORNs-D-M bind in a non-specific way to the receptor-binding domain of the HA protein. The ligand’s affinity to the hemagglutinin was estimated at the micromolar level. Presented experimental data confirmed that both natural ORNs and functionalized ORNs-D-M inhibit the interactions between HA and glycan receptors and demonstrate anti-influenza activity.

Highlights

Influenza epidemic activity causes significant morbidity and mortality
The World Health Organization (WHO) estimated that the 2009 pandemic alone caused 100,000–400,000 deaths, among groups considered to be at a higher risk of complications, such as the elderly, persons with chronic conditions, and pregnant women and in the group of young, healthy individuals
To study the interaction of ORNs and ORNs-D-M with the HA influenza virus, we used the isolated hemagglutinin in the form of vaccine “Vaxigrip”

Summary

Introduction

Influenza epidemic activity causes significant morbidity and mortality. It increases the costs of health services and contributes to economic losses due to absence from work. The World Health Organization (WHO) estimated that the 2009 pandemic alone caused 100,000–400,000 deaths, among groups considered to be at a higher risk of complications, such as the elderly, persons with chronic conditions, and pregnant women and in the group of young, healthy individuals. The annual trivalent or quadrivalent vaccines are the most effective way to prevent infection and severe outcomes caused by influenza viruses. Due to rapid antigenic drift and shift in influenza viruses, the selection of appropriate vaccine strains is a formidable task [1,2,3]. In connection with the emergence of resistance to existing licensed anti-influenza drugs and the constant threat of an epidemic or pandemic of influenza virus, it is an urgent need to search for a new antiviral drug against new targets [4,5,6]

Methods

Results

Conclusion