Chemoreactive-Inspired Discovery of Influenza A Virus Dual Inhibitor to Block Hemagglutinin-Mediated Adsorption and Membrane Fusion

Owing to the emergence of drug resistance
and high morbidity and
mortality, the need for novel anti-influenza A virus (IAV) drugs with
divergent targets is highly sought after. Herein, we reveal the discovery
of an anti-IAV agent as a dual inhibitor to block hemagglutinin-mediated
adsorption and membrane fusion using a chemoreactive ortho-quinone methide (o-QM) equivalent. Based on the o-QM equivalent nonenzymatically multipotent behavior, we
created a series of clavatol-derived pseudo-natural products and found
that penindolone (PND), a new diclavatol indole adduct, exhibited
potent and broad-spectrum anti-IAV activities with low risk of inducing
drug resistance. Distinct from current anti-IAV drugs, PND possesses
a novel scaffold and is the first IAV inhibitor targeting both HA1
and HA2 subunits of virus hemagglutinin to dually block the IAV adsorption
and membrane fusion process. More importantly, intranasal and oral
administration of PND can protect mice against IAV-induced death and
weight loss, superior to the effects of the clinical drug oseltamivir.
Thus, the use of chemoreactive intermediates could expand our understanding
of chemical diversity and aid in the development of anti-IAV drugs
with novel targets.