Key Laboratory of Protein and Peptide Pharmaceuticals, Beijing Translational Center for Biopharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
Beijing National Laboratory for Molecular Sciences, Center for Soft Matter Science and Engineering, Key Laboratory of Polymer Chemistry and Physics of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing, 100871, China.
Angew Chem Int Ed Engl. 2022 Feb 1;61(6):e202115241. doi: 10.1002/anie.202115241. Epub 2021 Dec 23.
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.
人α-1-抗胰蛋白酶（A1AT）是一种天然的丝氨酸蛋白酶抑制剂，可防止组织损伤免受过度蛋白酶活性的影响，被用作增敏疗法来治疗 A1AT 缺乏症患者。然而，A1AT 易受到氧化介导的失活，且体内循环半衰期较短。目前，尚无方法可有效保护治疗性蛋白免受体内氧化损伤。在这里，我们开发了一种新型的生物相容性硒多肽，并将其定点偶联到 A1AT 上。偶联后的 A1AT 完全保留了对中性粒细胞弹性蛋白酶的抑制活性，增强了抗氧化能力，延长了血清半衰期，并在急性肺损伤的小鼠模型中提供了持久的保护效果。这些结果表明，用设计的硒聚合物偶联 A1AT 是一种可行的策略，可以改善其药理学特性，这可能进一步应用于各种氧化敏感的生物治疗药物。
