Quadruplex-interacting compounds for regulating the translation of the Epstein–Barr virus nuclear antigen 1 (EBNA1) mRNA: A new strategy to prevent and treat EBV-related cancers
Résumé
he Epstein–Barr (EBV) virus is linked to at least 1% of human cancers that include Burkitt's and Hodgkin's lymphomas, nasopharyngeal carcinoma, and 10% of gastric cancers. EBV is a latent virus that possesses a genome maintenance protein, EBNA1, which is both essential for the virus and highly antigenic. Hence, EBV has evolved a mechanism by which EBNA1 self-limits the translation of its own mRNA, thereby minimizing the production of EBNA1-derived antigenic peptides. Although not fully elucidated, this mechanism involves the Gly-Ala-rich (GAr) motif of EBNA1, encoded by a G-repeat-containing mRNA sequence able to form clusters of G-quadruplexes (G4s). This chapter summarizes recent significant advances in understanding this phenomenon. Mechanistic investigations based on yeast chemical genetics, cellular assays and in vitro experiments have shown that the host cell factor nucleolin (NCL) is involved in this limitation of EBNA1 translation through binding to the G4s of EBNA1 mRNA. This interaction can be disrupted by the benchmark G4-ligand PhenDC3 acting as a NCL competitor for binding to G4-RNA. Finally, exploration of the chemical space around PhenDC3 using combinatorial chemistry approach led to the generation of 20 compounds based on a bis(acylhydrazone) scaffold. Among these, two hits (PyDH2, PhenDH2) exhibit optimized properties with regard to the disruption of NCL/G4 interaction in cells, along with lower cytotoxicity. Consequently, treatment by PyDH2 or PhenDH2 increases EBNA1 production and stimulates the GAr-restricted antigenic response. Altogether, this innovative concept of antigenic stimulation sets the basis for further identification of lead candidates that may become promising candidate drugs for treating EBV-related cancers