Optimization of Small-Molecule Inhibitors of Influenza Virus Polymerase: From Thiophene-3-Carboxamide to Polyamido Scaffolds

Abstract

Influenza virus infections represent a serious concern to public health, being characterized by high morbidity and significant mortality. To date, compounds targeting the viral ion-channel M2 or the viral neuraminidase are the drugs available for treatment of influenza, but the emergence of drug-resistant viral mutants renders the search for novel targets and their possible inhibitors a major priority. Recently, we demonstrated that the viral RNA-dependent RNA polymerase (RdRP) complex can be an optimal target of protein-protein disruption by small molecules, with thiophene-3-carboxamide derivatives emerging as promising candidates for the development of new anti-influenza drugs with broad-spectrum activity. Here, we report a further dissection of the thiophene-3-carboxamide structure. By using a GRID molecular interaction field (MIF)-based scaffold-hopping approach, more potent and nontoxic polyamido derivatives were identified, highlighting a new space in the chemical variability of RdRP inhibitors. Finally, a possible pharmacophoric model highlighting the key features required for RdRP inhibition is proposed.

A Broad Anti-influenza Hybrid Small Molecule That Potently Disrupts the Interaction of Polymerase Acidic Protein–Basic Protein 1 (PA-PB1) Subunits

“…While no small molecule targeting PB1-PB2 interaction is known, with only a few short peptides reported for this activity, 16,17 various small molecules able to disrupt the interactions between the PA and PB1 subunits have emerged during the last three years. [18][19][20][21][22][23][24][25] Their PPI inhibitory activity correlated to the inhibition of viral RdRP activity and of virus replication in cellular context, thus validating this antiviral strategy. Different approaches led to identify the PA-PB1 small molecule inhibitors reported so far ( Figure 1).…”

“…22 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 generation using FLAPpharm algorithm 43 was recently described. 24 Here, the pharmacophore was used as a template to run the FLAP virtual screening module. shifts are given in ppm (δ) and the spectral data are consistent with the assigned structures.…”

“…Since the H-bond acceptor and H-bond donor pharmacophoric points underneath the amide group proved to be essential for pharmacophore definition, 24 the presence of an inverse amide group linking the triazolopyrimidine core and the phenyl ring was studied by synthesizing the couple of positional isomers 34 and 35.…”

The Influenza Virus Polymerase Complex: An Update on Its Structure, Functions, and Significance for Antiviral Drug Design

“…D). This was followed by rational development of diverse lead compounds, some of which were used to generate a pharmacophore model for PA C ‐PB1 N interaction inhibitors . For the recently identified inhibitor ANA‐1 (Fig.…”

Targeting Influenza A Virus RNA Promoter

“…Similar to compound 1 , these molecules might not exhibit cellular anti‐influenza activity, perhaps due to premature degradation, limited cell permeability, binding to other targets, etc. In this regard, recent work clearly suggests that direct inhibition of RdRp targeting PB1–PA interactions with small molecules can be a viable target for inhibition of viral replication in both influenza A and B viruses . While we cannot rule out that our compounds may also directly affect RdRp in a similar fashion, our molecules do not share any structural features that resemble the reported chemical inhibitors of PB1–PA interactions .…”