In Silico Design of New Inhibitors Against Hemagglutinin of Influenza

The Journal of Physical Chemistry B 2019

DOI: 10.1021/acs.jpcb.8b10767

The RNA virus Influenza A is a serious public health problem with every year
epidemics resulting in more than 250,000 deaths. A protein cavity was identified
on the HA2 subunit of the hemagglutinin responsible for the entry of the virus into
the host cell by endocytosis. The binding of a ligand in this zone rich in invariant
residues and synthetic lethal couples, could prevent therapeutic escape and inhibit the
conformational change at pH=5 initiating the membrane fusion in the endosome. Two
pentapeptides, a linear peptide (EQRRS) and a cyclic peptide (DQRRD) have been
proposed as potential ligands. Complex stability and the interactions between the
ligand and the protein have been studied with the help of molecular dynamics and
quantum chemistry methods. A high stability of the interactions has been obtained
for these two ligands at both pH=7 and pH=5. Indeed, these two peptides present
two cooperative modes of action that should prevent the conformational change at the
origin of the spring-loaded mechanism at pH=5, (1) mechanical since they are docked
on HA2, and (2) electronic since they modify the protonation states of key residues in
the hairpin zone. This study thus paves the way towards the development of peptide
ligands that can inhibit the membrane fusion process.



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