Rational design of 2H-chromene-based antiphytovirals that inhibit virion assembly by outcompeting virus capsid-RNA interactions

Although the determination of the structural basis of potato virus Y (PVY) coat protein (CP) provides the possibility for CP-based antiviral drug design, the role of many specific residues on CP in regulating virion pathogenicity is largely unknown, and fewer small-molecular drugs have been discovered to act on these potential sites. In this study, a series of derivatives of 2,2-dimethyl-2<i>H</i>-chromene are rationally designed by employing a molecular hybridization strategy. We screen a case of phytovirucide <b>C50</b> that could form a stable H-bond with Ser¹²⁵ of PVY CP to exert antiviral properties. Ser¹²⁵ is further identified to be crucial for CP-viral RNA (vRNA) interaction, enabling PVY virion assembly. This interaction can be significantly inhibited through competitive binding with compound <b>C50</b>. The study enhances our understanding of anti-PVY drug mechanisms and provides a basis for developing new CP-targeting virus particle assembly inhibitors.