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Development of new bioselective ligation reactions

Authors
  • Koniev, Oleksandr
Publication Date
Mar 20, 2014
Source
HAL-UPMC
Keywords
Language
English
License
Unknown
External links

Abstract

Chemical ligation involves the linking of molecules in covalent manner to form a novel complex having the combined properties of its individual components. Thus, natural or synthetic compounds with their individual activities can be chemically combined to create unique substances possessing carefully engineered characteristics. A field of especial interest in such ligation procedures is protein labeling.To accelerate the discovery of new bioselective ligation reactions, we designed a screening system for fast assigning of the selectivity and reactivity of a given functional group owards series of UVGtraceable amino acid derivatives. As a result of our screening a promising cysteineGselective scaffold–3Garylpropiolonitrile (APN)–was identified. Its remarkable selectivity, high reactivity and of both starting and addition products in aqueous and organic media represents an important advantage compared to methodologies classically used for cysteine tagging. StructureGreactivity study allowed us to optimise its properties and toprepare a series of funcional probes, one of which was used for!an accurate test of APN selectivity on model mixtures of peptides. Furthermore, APN were found to possess an elevated selectivity towards selenocysteine:ararebut very important amino!acid found in many active enzymes.A series of APN was tested for their inhibitory activity towards one of such selenocysteineGcontaining enzyme–thioredoxine reductase–and was found to possess promising activities, which however still must be!optimised.Lastly, a screening system devoted to the discovery of reagents reactivity towards a sequence of amino acid residue was elaborated and allowed us to determine presumable discrepancy in reactivity of APN depending on the amino acid residue neighbouring the cysteine moiety. Such difference in reactivity may represent an important advantage for bioconjugation, and is currently under further investigation.

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