Target discovery of inhibitors based on a G-quadruplex structure in the potato virus Y genome

Potato virus Y (PVY) exhibits a wide host range and significantly affects crop growth. Development of novel targets is an important way to discover highly active PVY inhibitors with novel structure. G-quadruplex (G4) structures formed by guanine-rich nucleic acid sequences, have emerged as validated therapeutic targets driving the development of novel antiviral and antitumor agents. The untranslated regions is a regulatory region for mRNA expression, and the G4s in this region can regulate gene expression.

Ten G4 structures were identified in the genome of PVY, one of which is located in the 3'-untranslated regions (PQS10) and has the putative function of regulating gene expression. Further studies revealed that PQS10 may be folded into the dimeric G4 with two planar G-quartets. The binding affinity for G-quadruplex-ligands to PQS10 was evaluated by isothermal titration calorimetry, and the results indicated that BRACO-19, RHPS4, and TMPyP4 exhibited a higher binding affinity with PQS10. BRACO-19, RHPS4, and TMPyP4 were found to stabilize PQS10 G4 structure, thereby enhancing the inhibitory effect of PQS10 on expression of the dual luciferase reporter gene. These three compounds were found to interact with PQS10 through intercalation into its lateral external loops, and significantly inhibit the expression of the PVY gene with more than 75% inhibition rate.

This study demonstrated that G4 structures in the PVY genome are essential regulatory elements for viral proliferation, and provided new strategies for suppressing PVY proliferation. © 2025 Society of Chemical Industry.