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Instruments / Technical Area	Publication Details	Published
I03-Macromolecular Crystallography	Exploring divalent conjugates of 5-N-acetyl-neuraminic acid as inhibitors of coxsackievirus A24 variant (CVA24v) transduction Emil Johansson , Rémi Caraballo , Georg Zocher , Nitesh Mistry , Niklas Arnberg , Thilo Stehle , Mikael Elofsson Rsc Advances 12, 2319 - 2331 DOI: 10.1039/D1RA08968D Diamond Proposal Number(s): [19691] Open Access Show Abstract ▼ 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.	Jan 2022
I03-Macromolecular Crystallography	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 , Daniel L. Hurdiss , Nitesh Mistry , C. David Andersson , Rebecca F. Thompson , Neil A. Ranson , Georg Zocher , Thilo Stehle , Niklas Arnberg , Mikael Elofsson International Journal Of Molecular Sciences 22 DOI: 10.3390/ijms22168418 Diamond Proposal Number(s): [19691] Open Access Show Abstract ▼ 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.	Aug 2021
I03-Macromolecular Crystallography	Pentavalent sialic acid conjugates block coxsackievirus A24 variant and human adenovirus type 37 – viruses that cause highly contagious eye infections Emil Johansson , Rémi Caraballo , Nitesh Mistry , Georg Zocher , Weixing Qian , C. David Andersson , Daniel L. Hurdiss , Naresh Chandra , Rebecca Thompson , Lars Frängsmyr , Thilo Stehle , Niklas Arnberg , Mikael Elofsson Acs Chemical Biology DOI: 10.1021/acschembio.0c00446 Open Access Show Abstract ▼ Abstract: Coxsackievirus A24 variant (CVA24v) and human adenovirus 37 (HAdV-37) are leading causative agents of the severe and highly contagious ocular infections acute hemorrhagic conjunctivitis and epidemic keratoconjunctivitis, respectively. Currently, neither vaccines nor antiviral agents are available for treating these diseases, which affect millions of individuals worldwide. CVA24v and HAdV-37 utilize sialic acid as attachment receptors facilitating entry into host cells. Previously, we and others have shown that derivatives based on sialic acid are effective in preventing HAdV-37 binding and infection of cells. Here, we designed and synthesized novel pentavalent sialic acid conjugates and studied their inhibitory effect against CVA24v and HAdV-37 binding and infection of human corneal epithelial cells. The pentavalent conjugates are the first reported inhibitors of CVA24v infection, and proved efficient in blocking HAdV-37 binding. Taken together, the pentavalent conjugates presented here form a basis for the development of general inhibitors of these highly contagious ocular pathogens.	Aug 2020
I03-Macromolecular Crystallography	Structure of Merkel cell polyomavirus capsid and interaction with its glycosaminoglycan attachment receptor Niklas J. Bayer , Dovile Januliene , Georg Zocher , Thilo Stehle , Arne Moeller , Bärbel S. Blaum Journal Of Virology DOI: 10.1128/JVI.01664-19 Diamond Proposal Number(s): [14602] Open Access Show Abstract ▼ Abstract: Merkel cell polyomavirus (MCPyV) is a human double-stranded DNA tumor virus. MCPyV cell entry is unique among the polyomavirus family as it requires the engagement of two types of glycans, sialylated oligosaccharides and sulfated glycosaminoglycans (GAGs). Here, we present crystallographic and cryo-electron microscopic structures of the icosahedral MCPyV capsid and analysis of its glycan interactions via NMR spectroscopy. While sialic acid binding is specific for α2-3-linked sialic acid and mediated by the exposed apical loops of the major capsid protein VP1, a broad range of GAG oligosaccharides bind to recessed regions between VP1 capsomers. Individual VP1 capsomers are tethered to one another by an extensive disulfide network that differs in architecture from previously-described interactions for other PyVs. An unusual C-terminal extension in MCPyV VP1 projects from the recessed capsid regions. Mutagenesis experiments show that this extension is dispensable for receptor interaction.	Jul 2020
I03-Macromolecular Crystallography	A sialic acid binding site in a human picornavirus Georg Zocher , Nitesh Mistry , Martin Frank , Irmgard Haehnlein-Schick , Jens-Ola Ekström , Niklas Arnberg , Thilo Stehle Plos Pathogens 10 (10) DOI: 10.1371/journal.ppat.1004401 PMID: 25329320 Open Access Show Abstract ▼ Abstract: The picornaviruses coxsackievirus A24 variant (CVA24v) and enterovirus 70 (EV70) cause continued outbreaks and pandemics of acute hemorrhagic conjunctivitis (AHC), a highly contagious eye disease against which neither vaccines nor antiviral drugs are currently available. Moreover, these viruses can cause symptoms in the cornea, upper respiratory tract, and neurological impairments such as acute flaccid paralysis. EV70 and CVA24v are both known to use 5-N-acetylneuraminic acid (Neu5Ac) for cell attachment, thus providing a putative link between the glycan receptor specificity and cell tropism and disease. We report the structures of an intact human picornavirus in complex with a range of glycans terminating in Neu5Ac. We determined the structure of the CVA24v to 1.40 Å resolution, screened different glycans bearing Neu5Ac for CVA24v binding, and structurally characterized interactions with candidate glycan receptors. Biochemical studies verified the relevance of the binding site and demonstrated a preference of CVA24v for α2,6-linked glycans. This preference can be rationalized by molecular dynamics simulations that show that α2,6-linked glycans can establish more contacts with the viral capsid. Our results form an excellent platform for the design of antiviral compounds to prevent AHC.	Oct 2014

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