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    化學所在蛋白質化學修飾與細胞輸送研究方面取得新進展
    2019-07-16 | 編輯: | 【 】【打印】【關閉

      蛋白質是生命活動的主要執行者,其對生命過程的調控多通過種類復雜、時空分辨的化學修飾實現。設計對細胞微環境具有響應性的化學修飾蛋白可以在分子水平上揭示蛋白質調控生命過程的化學本質,并發展疾病診斷和治療的分子工具。 

      在國家自然科學基金委、科技部和中國科學院的支持下,中科院活體分析化學重點實驗室汪銘課題組圍繞蛋白質的化學修飾和細胞輸送開展研究,發展了系列對細胞微環境具有刺激響應性的蛋白質化學修飾新方法(Acc. Chem. Res., 2019, 52, 665-675)。最近,他們設計了還原性細胞微環境響應的蛋白質化學修飾方法,并利用腫瘤細胞內高濃度的還原性物質(如還原性谷胱甘肽等)調控核糖核酸酶(RNase A)的化學修飾,實現了蛋白質活性的細胞原位激活(Chem. Commun., 2019, 55, 5163-5166),并有望用于發展疾病靶向治療新策略。 

      同時,面對蛋白質穩定性差且難以穿透細胞膜的挑戰,他們與實驗室于萍研究員等合作,通過調控金屬-有機框架材料(ZIF-90)和蛋白質的組裝,發展了蛋白質細胞輸送和化學修飾調控新策略。他們發現,通過主客體化學作用,ZIF-90可攜帶小分子進入細胞,并對細胞內ATP具有響應性,進而實現了細胞ATP的選擇性實時熒光成像(J. Am. Chem. Soc., 2017, 139, 5877-5882)。在此基礎上,他們發展了具有普適性的ZIF-90和蛋白質組裝新方法,制備了多種ZIF-90和蛋白質納米顆粒,包括綠色熒光蛋白(GFP),核糖核酸酶A RNase A, 超氧化物歧化酶(SOD)和基因編輯蛋白(Cas9)等。研究發現,上述納米顆粒可高效輸送多種蛋白質進入細胞,并在細胞內ATP的作用下釋放蛋白質,進而實現了由細胞內活性氧調控和激活化學修飾蛋白。基于上述原理和方法,他們發展了ATP調控的CRISPR/Cas9基因編輯蛋白細胞輸送和基因編輯新方法,為進一步探索CRISPR/Cas9基因編輯的化學生物學和生物醫學應用提供了新工具。相關研究成果發表在近期J. Am. Chem. Soc.2019,141(9), 3782-3786),并入選雜志封面。 

     

     

      活體分析化學重點實驗室 

      201979   

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