Site-Specific Conjugation of a Selenopolypeptide to Alpha-1-antitrypsin Enhances Oxidation Resistance and Pharmacological Properties, Angew Chem Int Edit, 12 Dec 2021
Specific Conjugation of a Selenopolypeptide to Alpha-1-antitrypsin Enhances Oxidation Resistance and Pharmacological Properties
Chao Dong, Guangqi Wu, Chen Chen, Xia Li, Rui Yuan, Liang Xu, Hui Guo, Jay Zhang, Hua Lu, Feng Wang
Abstract
Human alpha-1-antitrypsin (A1AT), a native serine-protease inhibitor that protects tissue damage from excessive protease activities, is used as an augmentation therapy to treat A1AT-deficienct patients. However, A1AT is sensitive to oxidation-mediated deactivation and has a short circulating half-life. Currently, there is no method that can effectively protect therapeutic proteins from oxidative damage in vivo. Here we developed a novel biocompatible selenopolypeptide and site-specifically conjugated it with A1AT. The conjugated A1AT fully retained its inhibitory activity on neutrophil elastase, enhanced oxidation resistance, extended the serum half-life, and afforded long-lasting protective efficacy in a mouse model of acute lung injury. These results demonstrated that conjugating A1AT with the designed selenopolymer is a viable strategy to improve its pharmacological properties, which could potentially further be applied to a variety of oxidation sensitive biotherapeutics.
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Site-Specific Conjugation of a Selenopolypeptide to Alpha-1-antitrypsin Enhances Oxidation Resistance and Pharmacological Properties, Angew Chem Int Edit, 12 Dec 2021
Angewandte Chemie International Edition, 12 December, 2021, DOI：https://doi.org/10.1002/anie.202115241
Specific Conjugation of a Selenopolypeptide to Alpha-1-antitrypsin Enhances Oxidation Resistance and Pharmacological Properties
Chao Dong, Guangqi Wu, Chen Chen, Xia Li, Rui Yuan, Liang Xu, Hui Guo, Jay Zhang, Hua Lu, Feng Wang
Abstract
Human alpha-1-antitrypsin (A1AT), a native serine-protease inhibitor that protects tissue damage from excessive protease activities, is used as an augmentation therapy to treat A1AT-deficienct patients. However, A1AT is sensitive to oxidation-mediated deactivation and has a short circulating half-life. Currently, there is no method that can effectively protect therapeutic proteins from oxidative damage in vivo. Here we developed a novel biocompatible selenopolypeptide and site-specifically conjugated it with A1AT. The conjugated A1AT fully retained its inhibitory activity on neutrophil elastase, enhanced oxidation resistance, extended the serum half-life, and afforded long-lasting protective efficacy in a mouse model of acute lung injury. These results demonstrated that conjugating A1AT with the designed selenopolymer is a viable strategy to improve its pharmacological properties, which could potentially further be applied to a variety of oxidation sensitive biotherapeutics.
文章链接：https://onlinelibrary.wiley.com/doi/10.1002/anie.202115241