Exploring the Effect of Structure-Based Scaffold Hopping on the Inhibition of Coxsackievirus A24v Transduction by Pentavalent N-Acetylneuraminic Acid Conjugates.

Emil Johansson,Rémi Caraballo,Niklas Arnberg,Georg Zocher,Daniel L Hurdiss,Rebecca F Thompson,Thilo Stehle,Mikael Elofsson,Neil A Ranson,Nitesh Mistry,C David Andersson

doi:10.3390/ijms22168418

Abstract

Coxsackievirus A24 variant (CVA24v) is the primary causative agent of the highly contagious eye infection designated acute hemorrhagic conjunctivitis (AHC). It is solely responsible for two pandemics and several recurring outbreaks of the disease over the last decades, thus affecting millions of individuals throughout the world. To date, no antiviral agents or vaccines are available for combating this disease, and treatment is mainly supportive. CVA24v utilizes Neu5Ac-containing glycans as attachment receptors facilitating entry into host cells. We have previously reported that pentavalent Neu5Ac conjugates based on a glucose-scaffold inhibit CVA24v infection of human corneal epithelial cells. In this study, we report on the design and synthesis of scaffold-replaced pentavalent Neu5Ac conjugates and their effect on CVA24v cell transduction and the use of cryogenic electron microscopy (cryo-EM) to study the binding of these multivalent conjugates to CVA24v. The results presented here provide insights into the development of Neu5Ac-based inhibitors of CVA24v and, most significantly, the first application of cryo-EM to study the binding of a multivalent ligand to a lectin.

Highlights

Viral pandemics have over the course of human civilization, caused the suffering and deaths of millions of human beings [1]
We previously reported on the design and synthesis of pentavalent Neu5Ac conjugates with pseudoradial topology that inhibit Coxsackievirus A24 variant (CVA24v) attachment to, and infection of, HCE cells [23]
We performed structure-based scaffold hopping on pentavalent Neu5Ac conjugates in an attempt to achieve a chelating binding to CVA24v, and evaluated the effect of the scaffold replaced compounds on CVA24v transduction

Summary

Introduction

Viral pandemics have over the course of human civilization, caused the suffering and deaths of millions of human beings [1]. The severe consequences of viral outbreaks and pandemics are currently on global display, with the ravaging covid-19 pandemic that have crippled societies causing serious and, potentially, long-lasting socio-economic effects at both a local level and on a global scale. Coxsackievirus A24 variant (CVA24v), an antigenic variant of coxsackievirus A24 (CVA24), has over the last decades caused two pandemics and several recurring outbreaks of the highly contagious eye infection acute hemorrhagic conjunctivitis (AHC) with >10 million estimated cases of the disease [2,3]. AHC generally resolves spontaneously within 1–2 weeks, and severe conditions are rare, the development of acute flaccid paralysis and even fatalities have been reported [5,6]. Treatment of AHC is supportive as neither vaccines nor antivirals are currently available to combat the infection

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