CFTR (Cystic fibrosis transmembrane conductance regulator), mutations of which cause cystic fibrosis, belongs to the ATP-binding cassette (ABC) transporter family. Transitions between open and closed states of CFTR are regulated by ATP binding and hydrolysis on the cytosolic nucleotide-binding domains. However, the nonsense mutation, which generates a premature termination codon (PTC) in the CFTR mRNA, leading to the generation of a truncated CFTR protein. Moreover, PTC-containing CFTR mRNAs are often degraded by nonsense-mediated mRNA decay (NMD). Nonsense suppression (readthrough) therapy restores protein function by selectively suppressing translation termination at PTCs.
SRI-37240 is a potent PTCs inhibitor that suppresses CFTR nonsense mutations.
Mechanically, this compound promotes readthrough by prolonging the translational pause that occurs at PTCs by reducing the abundance of the termination factor, eRF1. In addition, SRI-37240 alters cellular translation termination at PTCs in HEK293T cells. SRI-37240 also increases the global densities of ribosomes at normal stop codons. Thus, SRI-37240 acts by inhibiting translation termination. However, it does not affect the densities of ribosomes in 3-UTRs. Specifically, in immortalized and primary human bronchial epithelial cells, SRI-37240 induces a prolonged pause at stop codons and suppresses PTCs associated with cystic fibrosis, restoring CFTR expression and function.
SRI-37240 can also restore CFTR function in primary bronchial epithelial cells when combined with G418. Moreover, SRI-37240 combined with G418 significantly increases the amount of full-length, fully glycosylated form of CFTR protein and the unprocessed, immature form of full-length CFTR protein. Importantly, SRI-37240 induces concentration-dependent increases in CFTR-dependent chloride conductance.
To sum up, SRI-37240 is a PTCs inhibitor that induces translational readthrough of CFTR nonsense mutations by eRF1 depletion.
 Jyoti Sharma, et al. Nat Commun. 2021 Jul 16;12(1):4358.