specific inhibition of nonsense-mediated mRNA decay by small molecule

The last step of protein synthesis is called translation termination. During this step the stop codon is recognized by the protein factor called "release factor" and finished protein is cleaved off the tRNA. Mutations which cause premature termination (nonsense mutations) lead to shortened protein which is usually defective, and in order to avoid accumulation of these proteins such mRNA are recognized by nonsense mediated mRNA decay (NMD) machinery and degraded.

This is usually a good thing, but imagine that the gene which has this nonsense mutation is very important for survival of the cell, and imagine that the truncated version is still somewhat functional. In this case it would be beneficial to produce it even if it is somewhat compromised: something is better than nothing.

Therefore in some cases NMD is actually a cause of a desease, such as Duchenne muscular dystrophy and cystic fibrosis - over-zealous NMD removes all the damaged mRNAs and no protein product is produced. In this case suppression of NMD is needed.

Treatment with antibiotic gentamicin wich causes error-prone translation is a solution, but unfortunately gentamicin is not specific for NMD and causes errors on all the steps of translation. Specific inhibition of NMD was sought after for many years, and finally a smal molecule which inhibits it was discovered.

The molecule is called PTC124, and we know that it does the trick (inhibits NMD) and works well against the DMD. It was discovered in 2007, and by now we still don't know to what it binds (ribosome? NMD factors?) and what is the mechanism. The reason for that is that it is extremely complicated to construct an in vitro system for studying PTC124 (you will need purified translational and NMD components, and that is a lot of components). So for now we have no idea how it works, but it does!

Update: ...or may be it doesn't!

References:

Welch EM, Barton ER, Zhuo J, Tomizawa Y, Friesen WJ, Trifillis P, Paushkin S, Patel M, Trotta CR, Hwang S, Wilde RG, Karp G, Takasugi J, Chen G, Jones S, Ren H, Moon YC, Corson D, Turpoff AA, Campbell JA, Conn MM, Khan A, Almstead NG, Hedrick J, Mollin A, Risher N, Weetall M, Yeh S, Branstrom AA, Colacino JM, Babiak J, Ju WD, Hirawat S, Northcutt VJ, Miller LL, Spatrick P, He F, Kawana M, Feng H, Jacobson A, Peltz SW, & Sweeney HL (2007). PTC124 targets genetic disorders caused by nonsense mutations. Nature, 447 (7140), 87-91 PMID: 17450125

Manuvakhova M, Keeling K, & Bedwell DM (2000). Aminoglycoside antibiotics mediate context-dependent suppression of termination codons in a mammalian translation system. RNA (New York, N.Y.), 6 (7), 1044-55 PMID: 10917599