Targeting eEF1A reprograms translation and uncovers broad-spectrum antivirals against cap or m⁶A protein synthesis...

Plitidepsin is an antitumoral compound safe for treating COVID-19 that targets the translation elongation factor eEF1A. Here we detect that plitidepsin decreases de novo cap-dependent translation of SARS-CoV-2 and non-viral RNAs but affects less than 13% of the host proteome, thus preserving cellular viability. In response to plitidepsin, cells upregulate EIF2AK3 and proteins that reduce translation, but also proteins that support proteostasis via ribosome synthesis and cap-independent translation by eIF4G2 and IGF2BP2. While plitidepsin inhibits cap- or internal ribosome entry sites (IRES)-mediated translation, its impact on N6-methyladenosine (m⁶A) translation is limited. In agreement, plitidepsin blocks members of Coronaviridae, Flaviviridae, Pneumoviridae and Herpesviridae families. Yet, it fails to inhibit retroviruses that exploit m⁶A synthesis routes and are blocked by drugs targeting IGF2BP2 m⁶A reader. By deciphering the molecular fingerprint of cells treated with therapies targeting translation we identify a rational approach to select broad-spectrum antivirals with potential to counteract future pandemic viruses.