Synthesis and evaluation of peptidic thrombin inhibitors bearing acid-stable sulfotyrosine analogues

Tyrosine sulfation is an important post-translational modification of peptides and proteins which underpins and modulates many protein-protein interactions. In order to overcome the inherent instability of the native modification, we report the synthesis of two sulfonate analogues and their incorpor...

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Bibliographic Details
Published in:Chemical communications (Cambridge, England) England), 2021-10, Vol.57 (83), p.1923-1926
Main Authors: Dowman, Luke J, Agten, Stijn M, Ripoll-Rozada, Jorge, Calisto, Bárbara M, Pereira, Pedro José Barbosa, Payne, Richard J
Format: Article
Language:English
Subjects:
Antithrombins - chemical synthesis
Antithrombins - chemistry
Antithrombins - metabolism
Crystallography
Crystallography, X-Ray
Enzyme Assays
Humans
Mimicry
Peptides
Peptides - chemical synthesis
Peptides - chemistry
Peptides - metabolism
Protein Binding
Proteins
Sulfation
Synthesis
Thrombin
Thrombin - antagonists & inhibitors
Thrombin - metabolism
Tyrosine
Tyrosine - analogs & derivatives
Tyrosine - chemistry
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Summary:Tyrosine sulfation is an important post-translational modification of peptides and proteins which underpins and modulates many protein-protein interactions. In order to overcome the inherent instability of the native modification, we report the synthesis of two sulfonate analogues and their incorporation into two thrombin-inhibiting sulfopeptides. The effective mimicry of these sulfonate analogues for native sulfotyrosine was validated in the context of their thrombin inhibitory activity and binding mode, as determined by X-ray crystallography. We describe the incorporation of two acid-stable mimics of sulfotyrosine into thrombin-inhibiting peptides and assess their activity and binding mode.
ISSN:1359-7345
1364-548X
DOI:10.1039/d1cc04742f