Eukaryotic Initiation Factor (eIF) Degrader

NVS1.1 is an orally active, blood-brain barrier-penetrant eRF1 degrader. NVS1.1 induces ubiquitination of eRF1 at Lys279, mediates proteasomal degradation via the E3 ubiquitin ligases RNF14 and RNF25 as well as the translational stress sensor GCN1, traps eRF1 at the ribosomal A-site, inhibits translation termination and triggers ribosome collision. As a readthrough enhancer, NVS1.1 enables near-cognate tRNA incorporation at premature termination codons by reducing intracellular eRF1 levels. NVS1.1 activates ribosome-associated quality control pathways via ribosome collision, including ubiquitination of small subunit ribosomal proteins. NVS1.1 restores functional full-length CFTR and IDUA proteins and reduces glycosaminoglycan accumulation in relevant models. NVS1.1 can be used in the research of cystic fibrosis and Hurler syndrome (mucopolysaccharidosis type I, MPS I).

NVS2.1 is a potent, orally active and brain-penetrant readthrough promoter. NVS2.1 triggers the degradation of eRF1 by activating the ribosome-related quality control pathways (involving GCN1, RNF14, and RNF25), thereby facilitating the reading through of premature termination codons. NVS2.1 can be used for the research of genetic diseases caused by nonsense mutations.