Small Molecules That Stabilize And Activate Lipoprotein Lipase (LPL)
Mikael Elofsson,
Professor,
University of Umeå
Hypertriglyceridemia is a frequently encountered lipid disorder in which plasma triglycerides (TG) levels are abnormally elevated. This condition is a risk factor of coronary artery disease and individuals suffering from severe hypertriglyceridemia may also develop acute pancreatitis. Plasma TG levels can be lowered with lifestyle changes such as low fat diet, physical training and alcohol restriction but medication is most often needed.
In the blood circulation, triglycerides are mostly found in large lipoproteins, forming their core. The clearance of these TG enriched lipoproteins is rapidly processed by lipoprotein lipase (LPL), a TG specific hydrolase enzyme that is active only as an unstable non-covalently associated homodimer. LPL activity is regulated by several endogenous cofactors e.g. Angptl3 and Angptl4 that inhibit the TG hydrolysis or promote its dissociation into inactive monomeric species.
We have employed a screening-based strategy to identify small molecules that stabilize and activate LPL. A medicinal chemistry program based on hit expansion and subsequent in vitro evaluation allowed establishment of structure-activity relationships. Continued improvement led to a series of compounds with efficacy in vivo. These compounds are currently being further explored with the goal to adevelop novel drugs to treat lipid disorders.
|
|
