Photochemically-enabled, post-translational production of C-terminal amides

IF 14.7 1区 综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES
David Hymel, Felix Wojcik, Kim S. Halskov, Wouter F. J. Hogendorf, Sydnee C. Wong, Ben M. Williams, Asmus R. Mortensen, Nick Cox, Ayesha Misquith, Nanna B. Holländer, Finn Matthiesen, Suneet Mehrotra, Michael R. Harris
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引用次数: 0

Abstract

C-terminal α-amidated peptides are attractive therapeutic targets, but preparative methods to access amidated pharmaceuticals are limited both on lab and manufacturing-scale. Here we report a straightforward and scalable approach to the C-terminal α-amidation of peptides and proteins from cysteine-extended polypeptide precursors. This amidation protocol consists of three highly efficient steps: 1) selective cysteine thiol substitution with a photolabel, 2) photoinduced decarboxylative elimination and 3) enamide cleavage by simple acidolysis or inverse electron demand Diels-Alder reaction. We provide a blueprint for applying this protocol to the semi-recombinant production of therapeutically relevant targets where gram scale C-terminal α-amidation is achieved in a photoflow reactor on a recombinantly prepared peptide YY analogue and a GLP-1/amylin co-agonist precursor peptide. Robust performance of this reaction cascade in flow highlights the potential of this chemistry to enable amidated drug leads to enter development that would not be viable on commercial scale using existing technology.

Abstract Image

光化学激活,翻译后产生c端酰胺
c端α-修饰肽是很有吸引力的治疗靶点,但获得修饰药物的制备方法在实验室和生产规模上都受到限制。在这里,我们报告了一种直接和可扩展的方法,用于半胱氨酸延伸多肽前体的肽和蛋白质的c端α-酰胺化。该酰胺化方案由三个高效步骤组成:1)用光标记选择性取代半胱氨酸硫醇,2)光诱导脱羧消除和3)通过简单酸解或逆电子需求Diels-Alder反应裂解酰胺。我们提供了将该方案应用于治疗相关靶标的半重组生产的蓝图,其中克级c端α-酰胺化在重组制备的肽YY类似物和GLP-1/amylin共激动剂前体肽的光流反应器中实现。这种反应级联在流动中的强劲表现突出了这种化学反应的潜力,使改性药物先导物进入开发阶段,而使用现有技术在商业规模上是不可行的。
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来源期刊
Nature Communications
Nature Communications Biological Science Disciplines-
CiteScore
24.90
自引率
2.40%
发文量
6928
审稿时长
3.7 months
期刊介绍: Nature Communications, an open-access journal, publishes high-quality research spanning all areas of the natural sciences. Papers featured in the journal showcase significant advances relevant to specialists in each respective field. With a 2-year impact factor of 16.6 (2022) and a median time of 8 days from submission to the first editorial decision, Nature Communications is committed to rapid dissemination of research findings. As a multidisciplinary journal, it welcomes contributions from biological, health, physical, chemical, Earth, social, mathematical, applied, and engineering sciences, aiming to highlight important breakthroughs within each domain.
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