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Influenza Virus – Viral entry and fusion inhibitor

February 7, 2020

Influenza epidemics affect millions of people
every winter. The human influenza virus is an enveloped ellipsoid-shaped virus of the Orthomyxoviridae family. This virus attacks respiratory system cells. The viral genome consists of 8 RNA segments
enclosed under the viral membrane. Each segment is associated with nucleocapsid
proteins and a polymerase complex. Haemagglutinin is an envelope protein located
on the surface of this virus. It plays an essential role in viral entry. It is organized in trimeric spike, each spike
comprising two subunits called HA1 and HA2, connected by a disulfide bridge. HA1 has a globular domain, which interacts
with the cellular receptor. HA2 is protected by HA1. It has a short sequence of hydrophobic residues called the fusion peptide at its amino-terminal end. It is anchored in the viral membrane via its
carboxy-terminal end. This subunit exhibits long helices oriented
perpendicular to the membrane. This helical architecture is characteristic
of class I membrane fusion proteins. Viruses are simple biological compounds that
need to infect cells to replicate. Influenza virus first interacts via its haemagglutinins with sialic acids anchored to the surface of the respiratory epithelial cells. This interaction initiates virus entry into
the targeted cell by endocytosis. A vesicle coated with clathrin is formed and
released into the cytoplasm. Transport vesicles are driven by molecular motors inside the cell where they fuse with early endosomes. Proton pumps present at the endosome membrane
acidify the vesicle lumen. Below pH 6, this acidification results in
important conformational changes in the haemagglutinin structure. HA1 moves away from HA2. Loop B connecting helices A and C rigidifies
and becomes helicoidal. As a consequence, the fusion peptide is projected away from the viral membrane and anchors in the endosome membrane. Helices C and D dissociate and helix D leans
onto helix C. This new rearrangement pulls the viral membrane
towards that of the endosome and the two membranes fuse together. A fusion pore is created and the viral genome
is released into the cell cytoplasm near the nucleus. The released viral ribonucleoprotein complexes carry nuclear localization signals. They enter the nucleus where the viral multiplication
process begins. New viral particles are synthesized with the
help of the cellular machinery. They bud off of the cell and infect new cells. Umifenovir is an antiviral molecule that blocks
the fusion mechanism. It carries an indole core and can bind strongly
to haemagglutinin, impeding its flexibility. During the acidification process of the endosome, haemagglutinin with bound umifenovir can no longer change its conformation. The fusion mechanism is blocked and the influenza
virus remains trapped in the endosome. The resulting late endosome fuses with a cell
lysosome to create an endolysosome. The whole influenza virus is then degraded
by the enzymes contained in this new cell compartment. Thus, the fusion inhibitor compound has played its curative role by preventing viral multiplication in the infected organism.

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