Chemically Stable Diazo Peptides as Selective Probes of Cysteine Proteases in Living Cells.

Autor: Wahl J; Freie Universität Berlin, Institute of Pharmacy - Medicinal Chemistry, GERMANY., Ahsanullah A; Freie Universität Berlin, Institute of Pharmacy - Medicinal Chemistry, GERMANY., Zupan H; Freie Universität Berlin, Institute of Chemistry and Biochemistry, GERMANY., Gottschalk F; Freie Universität Berlin, Institute of Pharmacy - Medicinal Chemistry, GERMANY., Nerlich A; Charité Universitätsmedizin Berlin, Department of Infectious Diseases, Respiratory Medicine and Critical Care, GERMANY., Arkona C; Freie Universität Berlin, Institute of Pharmacy - Medicinal Chemistry, GERMANY., Hocke AC; Charite Universitatsmedizin Berlin, Department of Infectious Diseases, Respiratory Medicine and Critical Care, GERMANY., Keller BG; Freie Universität Berlin, Institute of Chemistry and Biochemistry, GERMANY., Rademann J; Freie Universitat Berlin, Institute of Pharmacy, Medicinal Chemistry, Königin-Luise-Str. 2+4, 14195, Berlin, GERMANY.
Jazyk: angličtina
Zdroj: Angewandte Chemie (International ed. in English) [Angew Chem Int Ed Engl] 2024 Oct 09, pp. e202411006. Date of Electronic Publication: 2024 Oct 09.
DOI: 10.1002/anie.202411006
Abstrakt: Diazo peptides have been described earlier, however, due to their high reactivity have not been broadly used until today. Here, we report the preparation, properties, and applications of chemically stable internal diazo peptides. Peptidyl phosphoranylidene-esters and amides were found to react with triflyl azide primarily to novel 3,4-disubstituted triazolyl-peptides. Nonaflyl azide instead furnished diazo peptides, which are chemically stable from pH 1-14 as amides and from pH 1-8 as esters. Thus, diazo peptides prepared by solid phase peptide synthesis were stable to final deprotection with 95% trifluoroacetic acid. Diazo peptides with the recognition sequence of caspase-3 were identified as specific, covalent, and irreversible inhibitors of this enzyme at low nanomolar concentrations. A fluorescent diazo peptide entered living cells enabling microscopic imaging and quantification of apoptotic cells via flow cytometry. Thus, internal diazo peptides constitute a novel class of activity-based probes and enzyme inhibitors useful in chemical biology and medicinal chemistry.
(© 2024 Wiley‐VCH GmbH.)
Databáze: MEDLINE
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