Exploring divalent conjugates of 5-N-acetyl-neuraminic acid as inhibitors of coxsackievirus A24 variant (CVA24v) transduction.

Emil Johansson,Thilo Stehle,Georg Zocher,Mikael Elofsson,Niklas Arnberg,Rémi Caraballo,Nitesh Mistry

doi:10.1039/d1ra08968d

Abstract

Coxsackievirus A24 variant (CVA24v) is responsible for several outbreaks and two pandemics of the highly contagious eye infection acute hemorrhagic conjunctivitis (AHC). Currently, neither prevention (vaccines) nor treatments (antivirals) are available for combating this disease. CVA24v attaches to cells by binding Neu5Ac-containing glycans on the surface of cells which facilitates entry. Previously, we have demonstrated that pentavalent Neu5Ac conjugates attenuate CVA24v infection of human corneal epithelial (HCE) cells. In this study, we report on the structure-based design of three classes of divalent Neu5Ac conjugates, with varying spacer lengths, and their effect on CVA24v transduction in HCE cells. In relative terms, the most efficient class of divalent Neu5Ac conjugates are more efficient than the pentavalent Neu5Ac conjugates previously reported.

Highlights

Acute haemorrhagic conjunctivitis (AHC) is a highly contagious eye infection.[1]
Members of the Picornaviridae engage a range of different cellular receptors facilitating attachment and entry. These include coxsackievirus and adenovirus receptor (CAR), decay accelerating factor (DAF, CD55), low density lipoprotein receptor (LDL-R), human P-selectin glycoprotein ligand-1 (PSGL-1), heparan sulfate, integrins, intercellular adhesion molecule-1 (ICAM-1), and glycan-containing receptors terminating in 5-N-acetyl-neuraminic acid (Neu5Ac).[7,8,9,10,11]
We have previously reported on the design and synthesis of pentavalent Neu5Ac conjugates of radial[18] and pseudoradial[17] topology (Fig. 1B), that inhibit coxsackievirus A24 variant (CVA24v) infection of human corneal epithelial (HCE) cells

Summary

Introduction

Acute haemorrhagic conjunctivitis (AHC) is a highly contagious eye infection.[1]. It is predominantly caused by two members of the Picornaviridae family, coxsackievirus A24 variant (CVA24v), an antigenic variant of the CVA24 strain, and enterovirus 70 (EV70).[2]. We have previously reported on the design and synthesis of pentavalent Neu5Ac conjugates of radial[18] and pseudoradial[17] topology (Fig. 1B), that inhibit CVA24v infection of HCE cells. The spacer fragments of such divalent C2–C2 linked Neu5Ac compounds are less likely to bind to the canyon as alpha anomeric Neu5Ac substituents are pointing towards the solvent. Synthesis of the C2–C9 linked class of divalent Neu5Ac compounds 16–21 started from the amino acetate salt 1,21 that 2322 | RSC Adv., 2022, 12, 2319–2331

Results

Conclusion