Targeting protein-RNA interactions with peptide inhibitors
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Date
2024
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Abstract
Protein-RNA interactions (PRIs) play an essential role in many cellular functions. Having a widely applicable strategy to develop methods that target such interactions is highly valuable.
RNA binding motif 20 (RBM20) is a protein that plays a vital role in heart function and mutations in RBM20 associated with dilated cardiomyopathy (DCM). Previous studies have identified the structure of the RBM20 domain that is bound to the specific RNA sequence. Targeting RNA-RBM20 interaction can be a good starting approach in treating cardiac disease, yet direct targeting of the PRI can be challenging. However, allosteric inhibition of the target protein would provide a way of selective inhibition. Stapled peptides of RBM20 were synthesized and evaluated in the biophysical experiments. As a result, synthesized peptides showed binding affinity to the target protein.
Heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNP A2/B1), which is also an RNA binding protein, is upregulated in various types of cancer where it affects the splicing of tumor suppressors and oncogenes. Peptide nucleic acids (PNAs) are proposed to be used as a scaffold to carry fragments that target a PRI binding site. In addition, another strategy was explored, called translational repression assay procedure (TRAP), to track the recognition of the RNA by hnRNP A2/B1. This assay was then employed in combination with the split-intein circuit ligation of peptides and proteins (SICLOPPS) technique for the screening of the macrocyclic peptides as inhibitors for hnRNP A2/B1. Peptides were evaluated by applying biophysical experiments that defined two peptides that are binding to hnRNP A2/B1. Optimization through alanine scanning revealed a derivate with a ~3-fold increase in binding affinity. Further investigation and analysis need to be carried out to obtain a potential peptide inhibitor of hnRNP A2/B1.
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Keywords
Protein-RNA interaction, Stapled peptides, Macrocyclic