Researchers discovered that conjugating alpha-1 antitrypsin (A1AT) with a novel selenopolypeptide that they designed was a viable strategy to improve its pharmacological properties, as published in Angewandte Chemie.
A1AT is primarily secreted by hepatocytes and works by limiting tissue damage, such as neutrophil elastase, when inflammation occurs. Alpha-1 antitrypsin deficiency (AATD) is a hereditary disorder in which the body does not produce enough A1AT.
Currently, the main treatment for AATD is the intravenous administration of A1AT; however, this treatment regime is expensive and burdensome (as it requires weekly transfusions). “Selenium-containing polymers have been developed for drug delivery, self-adaptive materials, and enzyme mimics.” the researchers wrote.
“We hypothesized that a selenium-containing polymer would be a promising conjugation ‘partner’ for protein therapeutics such as A1AT to enhance their pharmacological properties,” they said, and hence decided to test out whether selenium-containing polypeptides (SePs) could protect A1AT from oxidative deactivation.
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They mixed different equivalents of selenopolypetides with A1AT and 100 equivalents of N-chlorosuccinimide (NCS) at room temperature for 30 minutes. In the absence of SePs, A1AT lost approximately 80% of neutrophil elastase inhibitory activity under oxidative conditions. However, when mixed with 8 equivalents of SeP2, approximately 50% of the inhibitory activity was retained.
The researchers then produced A1AT-SeP conjugates to measure their neutrophil elastase inhibitory abilities. They incubated 200 equivalents of NCS with A1AT, A1AT mixing with equivalent SePs, and A1AT-SeP conjugates for a total of 30 minutes.
“As expected, A1AT almost lost all of its inhibitory activity, while A1AT-SeP conjugates showed stronger antioxidant activity than A1AT mixed with equal equivalent SePs,” they concluded.
“We demonstrated that the SeP-A1AT conjugate showed strong and long-lasting antioxidant activities in vitro and in a mouse model. In addition, the conjugation of SePs significantly extended the circulation half-life of A1AT, which could facilitate the development of a long-acting therapy.”
Dong C, Wu G, Chen C, et al. Site-specific conjugation of a selenopolypetide to alpha-1-antitrypsin enhances oxidation resistance and pharmacological properties. Angew Chem Int Ed Engl. Published online December 12, 2021. doi:10.1002/anie.202115241