Aptamer Prevents Serpin Misfolding without Damaging Protease Inhibition

Aptamers are useful in biotechnological and therapeutic applications as they offer molecular recognition properties that rival that of antibodies. In addition to their discriminate recognition, aptamers offer advantages over antibodies, as they can be engineered completely in a test tube, are readily produced by chemical synthesis, possess desirable storage properties, and elicit little or no immunogenicity in therapeutic applications. Relative to monoclonal antibodies, aptamers are small, stable, and non-immunogenic.

Most serpins are fast and specific inhibitors of extracellular serine proteases controlling biological processes such as blood coagulation, fibrinolysis, tissue remodeling, and inflammation. The acronym serpin was originally coined because the first serpins to be identified acted on chymotrypsin-like serine proteases (serine protease inhibitors).

The inhibitory activity of serpins is based on a conserved metastable structure and their conversion to a more stable state during reaction with the target protease. However, the metastable state also makes serpins vulnerable to mutations, resulting in disease caused by inactive and misfolded monomeric or polymeric forms (“serpinopathy”). Misfolding can occur either intracellularly (type-I serpinopathies) or extracellularly (type-II serpinopathies). Most drug candidates that have been designed to prevent serpin misfolding also inhibit the anti-proteolytic functions of the serpins.

Investigators at Aarhus University (Denmark) reported in the June 2, 2016, online edition of the journal Cell Chemical Biology that they had isolated a 2′-fluoropyrimidine-modified RNA aptamer, which inhibited a mutation-induced inactivating misfolding of the serpin alpha1-antichymotrypsin.

The investigators claimed that this aptamer was the first agent able to stabilize a type-II mutation of a serpin without interfering with the inhibitory mechanism, thereby presenting a solution for the long-standing challenge of preventing pathogenic misfolding without compromising the inhibitory function.

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Aarhus University