Chemical genomics, bioactive molecules and alternative reading frame proteins: clues to sudden cardiac death

The cardiac drug flecainide was developed to prevent and treat serious ventricular tachycardia arrhythmias - very rapid heart rates which, if unchecked, can be lethal. However, in clinical trials, flecainide and its sister molecular encainide were reported to more than double the risk of sudden cardiac death.

Joint work by researchers in Chemistry and Medicine at the University of Warwick, and at the Biotech Company SEEK, is now allowing insight into how cardiac death risk might be increased by these drugs. The methods involve persuading viruses to provide a read-out on their surface of proteins related to human diseases.

In experiments just published in the Royal Society of Chemistry journal Chem Comm, we show that proteins from the heart may be read abnormally - through slippage in the letters of the genetic code for heart muscle components - these are called alternative reading frame proteins, a bit like a very simple old cipher.

Furthermore, flecainide is able to interact with a particular abnormally read protein. Previous research has linked this type of abnormality to serious side-effects of a drug used to treat the developing world parasitic infection Schistosomiasis.

There are two obvious implications of our new work. Testing for these abnormal proteins could be a new way to identify people and their family members who should be protected from risk of serious cardiac problems - for example by avoiding triggers of heart arrhythmias and by considering implantable defibrillators.

And by understanding how flecainide interacts with the abnormal protein, there may be clues to new treatments to interfere with the part of protein linked to cardiac problems.

Adverse effects of drugs can be very serious. When chosing a medicine, prescribers need to be aware of the balance of risks and benefits, and to chose the right drug for the right patient and the right disease, at the right time and for the right duration - long enough but not too long.

However our work shows an unexpected consequence of adverse effects of a drug: providing clues to new causes for disease and new ideas for treatments.