Influenza viruses are highly infectious and are the leading cause of human
respiratory diseases and may trigger severe epidemics and occasional pandemics. Although
antiviral drugs against influenza viruses have been developed, there is an urgent need to design new strategies to develop influenza virus inhibitors due to the increasing resistance of viruses toward currently available drugs. In this study, we examined the
antiviral activity of natural compounds against the following influenza virus strains: A/WSN/33 (H1N1), A/Udorn/72 (H3N2), and B/Lee/40.
Papaverine (a nonnarcotic
alkaloid that has been used for the treatment of
heart disease, impotency, and
psychosis) was found to be an effective inhibitor of multiple strains of influenza virus. Kinetic studies demonstrated that
papaverine inhibited influenza virus
infection at a late stage in the virus life cycle. An alteration in influenza virus morphology and viral
ribonucleoprotein (vRNP) localization was observed as an effect of
papaverine treatment.
Papaverine is a well-known
phosphodiesterase inhibitor and also modifies the
mitogen-activated protein kinase (MAPK) pathway by downregulating the phosphorylation of
MEK and
extracellular signal-regulated kinase (ERK). Thus, the modulation of host cell signaling pathways by
papaverine may be associated with the nuclear retention of vRNPs and the reduction of influenza virus titers. Interestingly,
papaverine also inhibited paramyxoviruses parainfluenza virus 5 (PIV5), human parainfluenza virus 3 (HPIV3), and respiratory syncytial virus (
RSV) infections. We propose that
papaverine can be a potential candidate to be used as an
antiviral agent against a broad range of influenza viruses and paramyxoviruses.IMPORTANCE Influenza viruses are important human pathogens that are the causative agents of epidemics and pandemics. Despite the availability of an annual
vaccine, a large number of cases occur every year globally. Here, we report that
papaverine, a
vasodilator, shows inhibitory action against various strains of influenza virus as well as the paramyxoviruses PIV5, HPIV3, and RSV. A significant effect of
papaverine on the influenza virus morphology was observed.
Papaverine treatment of influenza-virus-infected cells resulted in the inhibition of virus at a later time in the virus life cycle through the suppression of nuclear export of vRNP and also interfered with the host cellular cAMP and
MEK/ERK cascade pathways. This study explores the use of
papaverine as an effective inhibitor of both influenza viruses as well as paramyxoviruses.