E3-hijacking molecular glues of RNA binding protein IGF2BP1 in ovarian cancer

Project Information

E3glueRBP

Grant agreement ID: 101038053

DOI

10.3030/101038053

Project closed

EC signature date 1 April 2021

Start date 1 May 2021

End date 30 April 2023

Funded under

• SPREADING EXCELLENCE AND WIDENING PARTICIPATION

Total cost

€ 159 815,04

EU contribution

€ 159 815,04

Coordinated by

INSTITUTO DE MEDICINA MOLECULAR JOAO LOBO ANTUNES
Portugal

Periodic Reporting for period 1 - E3glueRBP (E3-hijacking molecular glues of RNA binding protein IGF2BP1 in ovarian cancer)

Reporting period: 2021-05-01 to 2023-04-30

Summary of the context and overall objectives of the project

During the COVID-19, vaccines and antiviral medications typically target proteins essential for viral infection and replication, causing the virus to mutate and diminish the effectiveness of conventional treatments. This involves the development of new vaccinations and medications. To get around this challenge, more and more researchers are turning to highly conserved sections of the viral RNA genome.
We developed a new approach to target and degrade the viral RNA genome by attaching imidazole to RNA, which destroyed the nucleic acid, and then attaching imidazole to an RNA-binding protein for targeted degradation. To target specific portions of the virus's genetic material, pyridostatin (PDS) and MTDB were utilized. PDS attaches to the RNA structure known as G-quadruplex (G4), whereas MTDB connects to betacoronaviral pseudoknots. We described these compounds proximity-induced nucleic acid degraders (PINADs) since they were attached with a flexible linker and imidazole.
This approach can turn any RNA-binding small molecule into a PINAD, which can then be utilized to target and eliminate other disease-related RNAs. This strategy could be utilized to treat other disorders that have previously proven difficult to target, such as Alzheimer's disease, or Huntington's disease, as well as cancer.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

Three projects were performed during this action support period: 1) development of a novel RNA degrader strategy -PINADs, to target viral RNA genome and successfully inhibit virus replication by testing in cell and mouse model; 2) discovery of a natural product Piperlongumine selectively induce reactive oxygen species in infected cells and acts as a host-directed pan-variant antiviral; 3) pre-clinical studies of a de novo decoy in K18-hACE2 mice model evaluating antiviral efficacy. All the works led to 3 publications (2 on ACS Central Science, 1 on Journal of Infectious Disease), 1 patent application, 2 international conferences presentations (EMBO Chem Bio 2022 in German, Gordon Research Conference 2023 in Boston), 3 seminars presentations (EU-funded Twinning projects), several press releases, and invited as round table speaker to European Researcher’s Night in Portugal 2022.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

The breakthroughs of our projects are: 1) instead of targeting proteins critical to viral infection and replication which may induces evolutionary pressure for the virus to mutate and reduce the effectiveness of existing treatments, we targeted the highly conserved structures with the viral RNA genome by PINADs strategy, or targeting the host cell by using Piperlongumine. Both methods highly improve the efficiency inhibiting emerging variants, and may even for other respiratory viruses. 2) the current RIBOTACs technique link small molecule RNA binders to ribonuclease L ligands, to create degraders that relied on ribonuclease expression within cells. To avoid this dependency, our PINADs strategy attach imidazole to RNA-binding molecule which could target and degrade the nucleic acid. This method could also be used to target and destroy other diseases-related RNAs.

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