Several diseases occur when mutations cause misfolding of proteins. These include "serpinopathies" which is a group of rare heritable diseases. They are caused by mutations of so-called "serpin" inhibitors of proteolytic enzymes involved in blood coagulation, tissue remodeling, and other important physiological functions. The mutations cause misfolding, which results in an inactive serpin and hence overactivity of the corresponding proteolytic enzyme.
The exact symptoms depend on which serpin is misfolded. The best known serpinopathy is α1-antitrypsin deficiency, which causes liver cirrhosis and lung emphysema. But also other serpins may misfold, for instance anti-thrombin and C1 inhibitor, leading to thrombosis and hereditary angioedema, respectively.
A long standing problem has been that agents preventing misfolding also inhibit the anti-proteolytic functions of the serpins. Working with a mutant of the serpin α1-antichymotrypsin, a group of Danish researchers has now designed a way of preventing misfolding while leaving the anti-proteolytic effect unabated. The α1-antichymotrypsin mutation is associated with chronic obstructive pulmonary disease (COPD).
The researchers have developed an RNA aptamer, which prevents misfolding and polymerisation of the α1-antichymotrypsin mutant and does not interfere with its ability to inhibit the target proteases, i.e., cathepsin G and chymotrypsin. One perspective is that similar strategies may be employed by other proteins prone to misfolding.