Enhancing RNA inhibitory activity using clamp-G-modified nucleobases.

We explore the potential of clamp-G nucleobase-modified peptide nucleic acids (cGPNAs) as microRNA and messenger RNA inhibitors. For proof of concept, we target miR-155, which is upregulated in diffuse large B cell lymphoma. cGPNA shows significant downregulation of miR-155 and the upregulation of its downstream targets in multiple lymphoma cell lines. Also, cGPNA treatment reduced tumor growth and improved survival in the U2932 cell-derived xenograft mouse model. To assess the broad application of cGPNA as an antisense modality, we also target transthyretin () mRNA. We establish a dose-dependent effect of antisense cGPNA on mRNA levels. For studies, we conjugated cGPNA-based TTR antisense with lactobionic acid-based targeting ligand for liver delivery. We establish that cGPNA exhibits significant TTR protein knockdown compared to unmodified peptide nucleic acid (PNA) . Overall, we confirm that clamp-G-modified PNA analogs are a robust antisense therapy platform.