Design, Optimization, and Study of Small Molecules That Target Tau Pre-mRNA and Affect Splicing.

ABSTRACT: Approximately 95% of human genes are alternatively spliced, and aberrant splicing events can cause disease. One pre-mRNA that is alternatively spliced and linked to neurodegenerative diseases is tau (microtubule-associated protein tau), which can cause frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) and can contribute to Alzheimer's disease. Here, we describe the design of structure-specific lead small molecules that directly target tau pre-mRNA from sequence. This was followed by hit expansion and analogue synthesis to further improve upon these initial lead molecules. The emergent compounds were assessed for functional activity in a battery of assays, including binding assays and an assay that mimics molecular recognition of tau pre-mRNA by a U1 small nuclear r

SUBMITTER: Chen JL 

PROVIDER: S-EPMC7357857 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature