Design of improved compounds to treat heart failure.
Heart failure is a serious condition which includes about 5 million people in the U.S., and results in about 300,000 deaths each year. Cardiac glycosides (CG) such as digoxin or digitoxin have been used for years to treat heart failure. However, CG might also cause toxic effects (e.g. induction of fatal cardiac arrhythmias). Both therapeutic and toxic cardiac effects of CG involve inhibition of Na,K-ATPase, the receptor for CG. One of its isoforms was found to have a central role of in cardiac signaling and contraction. Therefore, a CG selective to this isoform is likely to be of great value for treatment of heart failure. The outlined technology provides such an isoform in its purified form and as a complex with other subunits.
• Design of a CG that is intrinsically safer than digoxin or digitoxin
• Purified proteins provide an experimental system allowing screening of drug effects on the separate isoforms
• Allows for the development of an improved CG, with beneficial cardiac effects and reduced cardiotoxic effects
• Human Na,K-ATPase isoforms are expressed in yeast, and are therefore readily available (as opposed to human heart muscle)
Na,K-ATPase (found in human heart as ?1, ?2 and ?3 isoforms) actively transports Na and K ions across cell membranes and maintains the normal electrochemical gradients of the cations, which regulate fluid and electrolyte balance. When Na,K-ATPase in heart cells is inhibited moderately by CG the heart muscle contracts more strongly. When, however, Na,K-ATPase is inhibited excessively, by a CG overdose, it can induce fatal arhythmias. The present technology may resolve this issue, by developing CG derivatives with selectivity for the ?2 isoform, which was shown to be important for cardiac function.