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A critical cellular surveillance mechanism that recognizes and eliminates aberrant RNAs containing premature termination codons (PTC) is termed as nonsense-mediated mRNA decay (NMD). PTCs containing mRNAs are rapidly degraded by the NMD machinery. By this mechanism, NMD can exacerbate the phenotypes of many disorders by preventing the synthesis of truncated protein products with normal functions. Therefore, there is an intense interest in identifying NMD inhibitors (small-molecule) for treating certain diseases where the protein products of the corresponding nonsense mRNAs are fully or partially functional. Small-molecule inhibitors that can modulate. The NMD pathway, including UPF1, UPF2, UPF3a, and UPF3b, is over-produced in human cancers and can stimulate immune escape. Thus, the NMD pathway is a recognized drug target for cancer therapy, but there are no current clinical tools to validate this for use in human populations. Our approach to the treatment of diseases caused by PTC mutations is the inhibition of NMD, which is regulated by UPF1. The UPF1 gene, also termed as a master regulator of NMD pathway offers a new target that has not been successfully explored until now. We will focus on the core functions of UPF1 to find new small molecule ATP mimetic that can be used as a chemical tool to define the function and drugability of the pathway. Such novel compounds targeting UPF1 functions can increase stop-codon readthrough to enable the production of mutated full-length proteins and mutant MHC class I peptides derived from these premature stop codon readthroughs. Inhibiting hUPF1 with a small molecule, which will generate translation readthrough, can create neoantigens by virtue of the amino acid which is added at a stop codon. In this sense, NMD (UPF1) inhibitors stimulate the tumour cell to make its own vaccine. Most cancer vaccines in clinical trials exploit mutated proteins; these vaccines include peptide products, viral assembly of genomic encoded mutated peptides, or mRNA synthesis that encodes mutated peptides in a patient specific manner. However, our approach to stimulate PTC readthrough with a small molecule, that drives the tumour to synthesize its own novel mutated peptides, is itself a novel approach for developing cancer vaccines.
Details
- Project's acronym:
- UGPG
- Financial Program Name:
- OPUS
- Organization:
- Narodowe Centrum Nauki (NCN) (National Science Centre)
- Agreement:
- Umowa nr UMO-2020/39/B/NZ7/02677 z dnia 2021-09-01
- Realisation period:
- 2021-09-01 - 2025-08-31
- Research team leader:
- dr hab. Sławomir Makowiec
- Team members:
-
- PI from PG dr hab. Sławomir Makowiec
- Realised in:
- Department of Organic Chemistry
- External institutions
participating in project: -
- ICCVS (Poland)
- Uniwersytet Gdański (Poland)
- Project's value:
- 3 098 035.00 PLN
- Request type:
- National Research Programmes
- Domestic:
- Domestic project
- Verified by:
- Gdańsk University of Technology
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