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Synthesis of multi-module low density lipoprotein receptor class A domains with acid labile cyanopyridiniumylides (CyPY) as aspartic acid masking groups

Low-density lipoprotein receptor class A domains (LA modules) are common ligand-binding domains of transmembrane receptors of approximately 40 amino acids that are involved in several cellular processes including endocytosis of extracellular targets. Due to their wide-ranging function and distributi...

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Autores principales: Neumann, Kevin, Vujinovic, Alex, Kamara, Saidu, Zwicky, André, Baldauf, Simon, Bode, Jeffrey W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: RSC 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10074552/
https://www.ncbi.nlm.nih.gov/pubmed/37034404
http://dx.doi.org/10.1039/d2cb00234e
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author Neumann, Kevin
Vujinovic, Alex
Kamara, Saidu
Zwicky, André
Baldauf, Simon
Bode, Jeffrey W.
author_facet Neumann, Kevin
Vujinovic, Alex
Kamara, Saidu
Zwicky, André
Baldauf, Simon
Bode, Jeffrey W.
author_sort Neumann, Kevin
collection PubMed
description Low-density lipoprotein receptor class A domains (LA modules) are common ligand-binding domains of transmembrane receptors of approximately 40 amino acids that are involved in several cellular processes including endocytosis of extracellular targets. Due to their wide-ranging function and distribution among different transmembrane receptors, LA modules are of high interest for therapeutic applications. However, the efficient chemical synthesis of LA modules and derivatives is hindered by complications, many arising from the high abundance of aspartic acid and consequent aspartimide formation. Here, we report a robust, efficient and general applicable chemical synthesis route for accessing such LA modules, demonstrated by the synthesis and folding of the LA3 and LA4 modules of the low-density lipoprotein receptor, as well as a heterodimeric LA3–LA4 constructed by chemical ligation. The synthesis of the aspartic acid-rich LA domain peptides is made possible by the use of cyanopyridiniumylides (CyPY) – reported here for the first time – as a masking group for carboxylic acids. We show that cyanopyridiniumylide masked aspartic acid monomers are readily available building blocks for solid phase peptide synthesis and successfully suppress aspartimide formation. Unlike previously reported ylide-based carboxylic acid protecting groups, CyPY protected aspartic acids are converted to the free carboxylic acid by acidic hydrolysis and are compatible with all common residues and protecting groups. The chemical synthesis of Cys- and Asp-rich LA modules enables new access to a class of difficult to provide, but promising protein domains.
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spelling pubmed-100745522023-04-06 Synthesis of multi-module low density lipoprotein receptor class A domains with acid labile cyanopyridiniumylides (CyPY) as aspartic acid masking groups Neumann, Kevin Vujinovic, Alex Kamara, Saidu Zwicky, André Baldauf, Simon Bode, Jeffrey W. RSC Chem Biol Chemistry Low-density lipoprotein receptor class A domains (LA modules) are common ligand-binding domains of transmembrane receptors of approximately 40 amino acids that are involved in several cellular processes including endocytosis of extracellular targets. Due to their wide-ranging function and distribution among different transmembrane receptors, LA modules are of high interest for therapeutic applications. However, the efficient chemical synthesis of LA modules and derivatives is hindered by complications, many arising from the high abundance of aspartic acid and consequent aspartimide formation. Here, we report a robust, efficient and general applicable chemical synthesis route for accessing such LA modules, demonstrated by the synthesis and folding of the LA3 and LA4 modules of the low-density lipoprotein receptor, as well as a heterodimeric LA3–LA4 constructed by chemical ligation. The synthesis of the aspartic acid-rich LA domain peptides is made possible by the use of cyanopyridiniumylides (CyPY) – reported here for the first time – as a masking group for carboxylic acids. We show that cyanopyridiniumylide masked aspartic acid monomers are readily available building blocks for solid phase peptide synthesis and successfully suppress aspartimide formation. Unlike previously reported ylide-based carboxylic acid protecting groups, CyPY protected aspartic acids are converted to the free carboxylic acid by acidic hydrolysis and are compatible with all common residues and protecting groups. The chemical synthesis of Cys- and Asp-rich LA modules enables new access to a class of difficult to provide, but promising protein domains. RSC 2023-01-24 /pmc/articles/PMC10074552/ /pubmed/37034404 http://dx.doi.org/10.1039/d2cb00234e Text en This journal is © The Royal Society of Chemistry https://creativecommons.org/licenses/by/3.0/
spellingShingle Chemistry
Neumann, Kevin
Vujinovic, Alex
Kamara, Saidu
Zwicky, André
Baldauf, Simon
Bode, Jeffrey W.
Synthesis of multi-module low density lipoprotein receptor class A domains with acid labile cyanopyridiniumylides (CyPY) as aspartic acid masking groups
title Synthesis of multi-module low density lipoprotein receptor class A domains with acid labile cyanopyridiniumylides (CyPY) as aspartic acid masking groups
title_full Synthesis of multi-module low density lipoprotein receptor class A domains with acid labile cyanopyridiniumylides (CyPY) as aspartic acid masking groups
title_fullStr Synthesis of multi-module low density lipoprotein receptor class A domains with acid labile cyanopyridiniumylides (CyPY) as aspartic acid masking groups
title_full_unstemmed Synthesis of multi-module low density lipoprotein receptor class A domains with acid labile cyanopyridiniumylides (CyPY) as aspartic acid masking groups
title_short Synthesis of multi-module low density lipoprotein receptor class A domains with acid labile cyanopyridiniumylides (CyPY) as aspartic acid masking groups
title_sort synthesis of multi-module low density lipoprotein receptor class a domains with acid labile cyanopyridiniumylides (cypy) as aspartic acid masking groups
topic Chemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10074552/
https://www.ncbi.nlm.nih.gov/pubmed/37034404
http://dx.doi.org/10.1039/d2cb00234e
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