The amyloidogenicity of the influenza virus PB1-derived peptide sheds light on its antiviral activity

Abstract

The influenza virus polymerase complex is a promising target for new antiviral drug development. It is known that, within the influenza virus polymerase complex, the PB1 subunit region from the 1 st to the 25 th amino acid residues has to be is in an alpha-helical conformation for proper interaction with the PA subunit. We have previously shown that PB1(6-13) peptide at low concentrations is able to interact with the PB1 subunit N-terminal region in a peptide model which shows aggregate formation and antiviral activity in cell cultures. In this paper, it was shown that PB1(6-13) peptide is prone to form the amyloid-like fibrillar aggregates. The peptide homo-oligomerization kinetics were examined, and the affinity and characteristic interaction time of PB1(6-13) peptide monomers and the influenza virus polymerase complex PB1 subunit N-terminal region were evaluated by the SPR and TR-SAXS methods. Based on the data obtained, a hypothesis about the PB1(6-13) peptide mechanism of action was proposed: the peptide in its monomeric form is capable of altering the conformation of the PB1 subunit N-terminal region, causing a change from an alpha helix to a beta structure. This conformational change disrupts PB1 and PA subunit interaction and, by that mechanism, the peptide displays antiviral activity.

Amyloid peptides with antimicrobial and/or microbial agglutination activity

“…The third mechanism is rarely reported. Zabrodskaya et al (2018) reported that the amyloid peptide PB1(6-13) (6-13 residues of basic polymerase 1) monomer, derived from the influenza A virus polymerase complex PB1, was found to interact with its matrix protein PB1 subunit N-terminal region, causing a conformation of PB1 shift toward beta structures, and making PB1 lost its ability to interact with the acidic polymerase subunit; as a result, the influenza virus' polymerase complex functionality was broken (Egorov et al 2013;Zabrodskaya et al 2018).…”

“…In addition, Juhl et al (2020) found the antimicrobial activities of peptidyl-glycineleucine-carboxyamide (PGLa) decreased with fibril formation. Besides, Zabrodskaya et al (2018) found that after the amyloid peptide PB1(6-13) monomer formation into fibrils, it was no longer able to interact with PB1 N-terminal region, nor was it able to exert antiviral activity. Different antimicrobial effectiveness are reported even for the same amyloid proteins.…”