A BODIPY-Tagged Phosphono Peptide as Activity-Based Probe for Human Leukocyte Elastase

• Published in: ACS medicinal chemistry letters Vol. 9; no. 4; pp. 345 - 350
• Main Authors: Schulz-Fincke, Anna-Christina, Blaut, Michael, Braune, Annett, Gütschow, Michael
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 12.04.2018; Amer Chemical Soc
• Subjects: Chemistry, Medicinal; Letter; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; human leukocyte elastase; phosphonates; copper-catalyzed azide−alkyne cycloaddition; BOPIPY derivatives; serine proteases; copper-catalyzed azide-alkyne cycloaddition; DESIGN; HUMAN NEUTROPHIL ELASTASE; FLUORESCENT REPORTERS; ENZYME; SUBSTRATE; HUMAN-DISEASES; PROTEINASE-3; CATHEPSIN-G; INHIBITORS
• ISSN: 1948-5875; 1948-5875
• DOI: 10.1021/acsmedchemlett.7b00533

Human leukocyte elastase plays a crucial role in a variety of inflammatory disorders and represents an important subject of biomedical studies. The chemotype of peptidic phosphonates was employed for the design of a new activity-based probe for human leukocyte elastase. Its structure combines the phosphonate warhead with an adequate peptide portion and a BODIPY fluorophore with a clickable ethinylphenyl moiety at meso position. The probe 6 was assembled by copper-catalyzed alkyne–azide 1,3-dipolar cycloaddition. It was characterized as an active site-directed elastase inhibitor exhibiting a second-order rate constant of inactivation of 88400 M–1s–1. The suitability of 6 as a fluorescent probe for human leukocyte elastase was demonstrated by in-gel fluorescence analysis. Labeling experiments and inhibition data toward a panel of related proteases underlined the selectivity of the probe for the targeted leukocyte elastase.