Abstract
Influenza (flu) virus is a serious threat to global health with the potential to generate devastating pandemics. The availability of broad spectrum antiviral drugs is an unequaled weapon during pandemic events, especially when a vaccine is still not available. One of the most promising targets for the development of new antiflu therapeutics is the viral RNA-dependent RNA polymerase (RdRP). The assembly of the flu RdRP heterotrimeric complex from the individual polymerase acidic protein (PA), polymerase basic protein 1 (PB1), and polymerase basic protein 2 (PB2) subunits is a prerequisite for RdRP functions, such as mRNA synthesis and genome replication. In this Review, we report the known protein–protein interactions (PPIs) occurring by RdRP that could be disrupted by small molecules and analyze their benefits and drawbacks as drug targets. An overview of small molecules able to interfere with flu RdRP functions exploiting the PPI inhibition approach is described. In particular, an update on the most recent inhibitors targeting the well-consolidated RdRP PA–PB1 subunit heterodimerization is mainly reported, together with pioneer inhibitors targeting other virus–virus or virus–host interactions involving RdRP subunits. As demonstrated by the PA–PB1 interaction inhibitors discussed herein, the inhibition of flu RdRP functions by PPI disrupters clearly represents a valid means to identify compounds endowed with a broad spectrum of action and a reduced propensity to develop drug resistance, which are the main issues of antiviral drugs.
Highlights
Influenza virus is a serious threat to global health with the potential to generate devastating pandemics
As demonstrated by the PA−PB1 interaction inhibitors discussed the inhibition of flu RNAdependent RNA polymerase (RdRP) functions by PPI disrupters clearly represents a valid means to identify compounds endowed with a broad spectrum of action and a reduced propensity to develop drug resistance, which are the main issues of antiviral drugs
The generation of new epidemic strains occurs during the process of antigenic drift, in which the viral error-prone RNAdependent RNA polymerase (RdRP) introduces mutations in the genes responsible for encoding the antigenic proteins HA and NA
Summary
Flu infections are responsible for annual epidemics associated with high medical costs. Compound 26 resulted in the most selectivity with SI values >3000, and its activity was comparable to or even higher than that observed for polymerase inhibitor favipiravir against flu A and B strains (EC50 values ranging from 0.083 to 3.1 μM, SI > 2000).[115] The propensity of PA−PB1 inhibitors to induce drug resistance was evaluated, showing that they are impressively refractory to select drug-resistant viral variants under high-dose selective pressure. The Review collects for the first time all the interactions occurring by RdRP subunits that could be disrupted by small molecules Their benefits and drawbacks as a drug target were analyzed, and this work offers scientists involved in the antiflu research field the opportunity to apply the PPI inhibition strategy toward new interfaces still unexplored.
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