Synthetic O-acetylated sialosides facilitate functional receptor identification for human respiratory viruses

Abstract

The transmission of viruses from animal reservoirs to humans poses major threats to public health. Preparedness for future zoonotic outbreaks requires a fundamental understanding of how viruses of animal origin have adapted to binding to a cell surface component and/or receptor of the new host. Here we report on the specificities of human and animal viruses that engage with O-acetylated sialic acid, which include betacoronaviruses, toroviruses and influenza C and D viruses. Key to these studies was the development of a chemoenzymatic methodology that can provide almost any sialate-acetylation pattern. A collection of O-acetylated sialoglycans was printed as a microarray for the determination of receptor specificity. These studies showed host-specific patterns of receptor recognition and revealed that three distinct human respiratory viruses uniquely bind 9-O-acetylated α2,8-linked disialoside. Immunofluorescence and cell entry studies support that such a glycotope as part of a ganglioside is a functional receptor for human coronaviruses.

Multivalent 9-O-Acetylated-sialic acid glycoclusters as potent inhibitors for SARS-CoV-2 infection

“…Besides homeostatic cellular function, AcSA are usurped as binding sites for several human pathogens, including viruses. One of the first entry points on the respiratory virus pathway is the airway epithelium, rich in 7/9-AcSA, that are therefore used as attachment sites by many respiratory viruses, such as influenza (C and D types 58 , 59 ) and coronaviruses (HCoV-OC43 and HCoV-HKU1 8 , 60 ). As cryo-EM has revealed a well-conserved binding pocket in many coronaviruses that engages 9-AcSA 11 , we sought to prove that SARS-CoV-2 could share the same binding properties towards this sialylated glycan.…”

Sialic acid O-acetylation: From biosynthesis to roles in health and disease

“…In contrast to IAV and IBV, influenza C (ICV) and D (IDV) viruses display only one multifunctional hemagglutinin esterase fusion (HEF) glycoprotein on their surface which mediates binding to Neu5,9Ac 2 (and Neu5Gc9Ac), uptake into host cells, and deacetylation during release of progeny virus (88,(218)(219)(220)(221) (Figure 3B). The X-ray crystal structure of ICV hemagglutinin shows that it contains a non-polar pocket to accommodate the 9-O-Ac group and a relaxed linkage specificity as 9-O-Ac-Sias on α2-3-linked, α2-6-linked, and α2-8-linked sialosides are recognized, although with a strong preference for the latter (222,223). The esterase domain in complex with a non-hydrolysable 9-O-Ac-Sia analogue was also characterized via X-ray crystallography confirming the binding mode of the acetyl group in a non-polar pocket (222).…”

“…The 2012 Middle East respiratory syndrome coronavirus (MERS-CoV) recognizes α2-3linked Neu5Ac as major ligand and 7/9-O-acetylation blocks binding (226). On the other hand, both endemic human coronaviruses HCoV-OC43 and HCoV-HKU1 that infect the upper respiratory tract and can cause the common cold bind Neu5,9Ac 2 , preferably on α2-8-sialosides (223,(227)(228)(229)(230) (Table 2). Like all coronaviruses, HCoV-OC43 and HCoV-HKU1 display a long (20 nm) trimeric spike glycoprotein (S) and additionally they express a shorter (8nm) hemagglutinin esterase (HE) glycoprotein (230).…”

Trendbericht Organische Chemie 2022

“…Verbindungen aus der Familie der Triacsine, wie Triacsin A (135), sind die einzige bislang bekannte Naturstoffklasse mit einem N-Hydroxytriazen-Strukturelement. Der Großteil des Kohlenstoffgerüsts in (135) wird durch Polyketidbiosynthese aus Malonat assembliert (blau dargestellt). 91) Ein weiterer wichtiger Baustein ist Glycin (grün), aus dem auch eines der drei N-Atome stammt.…”