Targeting eEF1A reprograms cellular translation and uncovers alternative broad-spectrum antivirals against cap or m6A protein synthesis routes
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ABSTRACT:
PROVIDER: PRJNA1126260 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR29481925_1.fastq.gz | Fastqsanger.gz | |||
| SRR29481925_2.fastq.gz | Fastqsanger.gz | |||
| SRR29481926_1.fastq.gz | Fastqsanger.gz | |||
| SRR29481926_2.fastq.gz | Fastqsanger.gz | |||
| SRR29481927_1.fastq.gz | Fastqsanger.gz |
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Project description:Plitidepsin is an antitumoral drug safe for treating COVID-19 infection that impairs SARS-CoV-2 replication by targeting the translation elongation factor eEF1A. Here we show that plitidepsin decreased all SARS-CoV-2 transcripts along the early translation of viral R1AB polyproteins and the late synthesis of structural viral proteins. It also reduced de novo cap-dependent translation of viral and non-viral RNAs but affected less than 13% of the host proteome, thus preserving cellular viability. In response to plitidepsin, cells upregulated EIF2AK3 and additional proteins that reduce translation. Other proteins supported proteostasis via ribosome synthesis and cap-independent translation routes, which relied on eIF4G2, PABPC1, and readers such as IGF2BP2. While cap- or internal ribosome entry sites (IRES)-mediated translation pathways were inhibited by plitidepsin, impact on N6-methyladenosine (m6A) translation was limited. The molecular landscape reprogrammed by cells treated with plitidepsin predicted a potential broad-spectrum activity against viruses translated via cap- or IRES-dependent pathways that were suppressed by m6A. In agreement, plitidepsin inhibited the replication of members from the Coronaviridae, Flaviviridae, Pneumoviridae and Herpesviridae families. Yet, it failed to block retroviruses that exploit m6A synthesis routes and are inhibited by drugs against specific m6A readers such as IGF2BP2. By deciphering the molecular fingerprint of cells treated with host-directed therapies targeting protein translation, we identified a rational approach to select for broad-spectrum antivirals with complementary activities and potential to counteract future pandemic viruses.
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Project description: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.
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Project description:Classical antiviral therapy inhibit viral proteins and are subject to resistance. To counteract this emergence, alternative strategy has been developed that target cellular factors. We hypothesized that such approach could also be useful to identify broad antivirals. Influenza A virus was used as a model for viral diversity and need for therapy against unpredictable viruses as recently underlined by the H1N1 pandemic. We proposed to identify a gene-expression signature associated with infection with different influenza A virus subtypes which could help to identify potential antiviral drugs with broad spectrum. Cellular gene expression response to infection with five different human and avian influenza viruses strains was analyzed and 300 genes were determined as differentially expressed between infected and non-infected samples. Strikingly, only a few genes were induced by infection and related to immune response. A more concise list was used to screen connectivity map, a database of drug-associated gene expression profiles, for molecules with inverse profiles than the signature of infection. We hypothesized that such compounds would induce an unfavorable cellular environment for influenza virus replication. Eight potential antivirals including ribavirin were identified, and six inhibited influenza viral growth in vitro. The new pandemic H1N1 virus, which was not used to define the gene expression signature of infection, was inhibited by five of the eight identified molecules, demonstrating that this strategy could help to identify broad spectrum antivirals. This is the first study showing that a gene expression based-screening can be used to identify antivirals. Such approaches could accelerate the drug discovery progress and could be extended to other pathogens.
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