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1.
Bioconjug Chem ; 35(3): 286-299, 2024 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-38451202

RESUMO

Chemoselective protein modification plays extremely important roles in various biological, medical, and pharmaceutical investigations. Mimicking the mechanism of the chemoselective reaction between natural azaphilones and primary amines, this work successfully simplified the azaphilone scaffold into much simpler 3-acyl-4-pyranones. Examinations confirmed that these slim-size mimics perfectly kept the unique reactivity for selective conjugation with the primary amines including lysine residues of peptides and proteins. The newly developed pyranone tool presents remarkably increased aqueous solubility and compatible second-order rate constant by comparison with the original azaphilone. Additional advantages also include the ease of biorthogonal combinative use with a copper-catalyzed azide-alkyne Click reaction, which was conveniently applied to decorate lysozyme with neutral-, positive- and negative-charged functionalities in parallel. Moderate-degree modification of lysozyme with positively charged quaternary ammoniums was revealed to increase the enzymatic activities.


Assuntos
Lisina , Muramidase , Lisina/química , Indicadores e Reagentes , Peptídeos/química , Aminas , Azidas/química , Química Click , Alcinos/química
2.
Angew Chem Int Ed Engl ; 61(6): e202111783, 2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-34825445

RESUMO

Residue-selective bioconjugation methods for biomolecules are highly sought to expand the scope of their biological and medical applications. Inspired by the mechanism of the generation of natural vinylogous γ-pyridones (vPDNs), we have developed a novel unique azaphilone-based, activation-free primary-amine-selective bioconjugation method for biomolecules. Our strategy allows facile functionalization of primary amine groups in peptides and proteins, including the clinically used therapeutic antibody trastuzumab, by generating a highly stable vPDN linkage. Excellent chemoselectivity toward primary amines also enables the azaphilone derivatives to specifically modify the lipid components of Gram-positive bacteria while bypassing Gram-negative bacteria and mammalian cells. The new method shows significant advantages including chemoselectivity, efficiency, flexibility and biocompatibility, and therefore provides a valuable addition to the current toolbox for biomolecule conjugation.


Assuntos
Aminas/química , Benzopiranos/química , Lipídeos/química , Peptídeos/química , Pigmentos Biológicos/química , Proteínas/química , Piridonas/síntese química , Estrutura Molecular , Piridonas/química
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