Targeting virus-glycan recognition in influenza viruses and coronaviruses: from the molecular principles to glycomimetic antivirals strategies.

Glycans constitute the first molecular landscape encountered by viruses during infection and play fundamental roles in viral attachment, host adaptation, tissue tropism, and immune evasion. Far from being passive components of the cell surface, host glycans actively regulate virus-host interactions by functioning as attachment factors, entry receptors, or modulators of receptor engagement, while viral glycans contribute to immune escape and infectivity. Consequently, the molecular recognition of glycans has emerged as a major determinant of viral evolution and pathogenicity. This review presents our perspective on the structural and mechanistic principles that govern virus-glycan recognition, focusing on influenza viruses and coronaviruses as paradigmatic examples. We discuss how subtle variations in glycan structure, including glycosidic linkage, chain length, multivalent presentation, and chemical modifications such as O-acetylation, shape viral receptor specificity, host range, and cross-species transmission. Recent advances from structural biology, NMR spectroscopy, glycan arrays, computational modeling, and glycochemistry have substantially expanded our understanding of these dynamic recognition events and their evolutionary consequences. We further highlight how these insights are driving the development of glycomimetic antivirals designed to interfere with the earliest stages of infection. Approaches based on multivalent sialoglycan analogues, stabilized carbohydrate mimetics, and heparan sulfate-inspired scaffolds illustrate the growing potential of targeting glycan-mediated recognition as an alternative or complementary antiviral strategy. By integrating molecular recognition, viral adaptation, and medicinal chemistry, this review underscores the opportunities offered by glycobiology to develop innovative, potentially broad-spectrum antiviral therapeutics.