Hemagglutinin-neuraminidase protein (HN) (HN)

The viral hemagglutinin-neuraminidase (HN) protein is a multifunctional surface glycoprotein essential for the life cycle of viruses in the Paramyxoviridae family, such as human parainfluenza viruses and mumps virus [5, 12]. Unlike influenza viruses, which utilize separate proteins for attachment and release, the HN protein integrates both hemagglutinin (receptor binding) and neuraminidase (sialic acid cleavage) functions into a single polypeptide [10, 12]. It mediates the initial attachment of the virus to sialic acid-containing receptors on the host cell surface and subsequently undergoes a conformational change that triggers the viral fusion (F) protein to facilitate membrane fusion and viral entry [13, 17]. During the late stages of infection, its neuraminidase activity cleaves sialic acid residues from host cells and progeny virions to prevent self-aggregation and enable the release of new viral particles [10, 19]. Because of its pivotal roles in entry, fusion, and exit, the HN protein is a major target for antiviral drug discovery and vaccine design [25, 26]. Therapeutic strategies include small-molecule inhibitors like BCX 2798 that block the neuraminidase active site, compounds that interfere with F-protein triggering, and host-directed agents like DAS181 that deplete cellular sialic acid receptors [26, 33, 38]. However, the high degree of structural variability among different paramyxoviruses and the potential for drug-resistant mutations present significant challenges for the development of broad-spectrum HN-targeted therapies [25, 31].

Other names

HN proteinHemagglutinin-neuraminidase glycoproteinSialidaseReceptor-binding proteinViral hemagglutinin-neuraminidase

The HN protein is targeted through several distinct mechanisms: competitive inhibition of the neuraminidase active site to prevent viral release (e.g., BCX 2798, Zanamivir), blocking of the hemagglutinin site to prevent host cell attachment, and inhibition of the conformational changes required to trigger the fusion (F) protein [26, 30, 37]. Additionally, novel strategies include the use of small molecules like CSC11 to induce premature activation of the F protein, rendering the virus non-infectious before it reaches the host membrane [33]. Host-directed therapies such as DAS181 (Fludase) act by enzymatically removing the sialic acid receptors from the respiratory epithelium, thereby depriving the HN protein of its binding substrate [38, 39].