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Development of Selective ADAMTS-5 Peptide Substrates to Monitor Proteinase Activity.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2023 Mar 09; Vol. 66 (5), pp. 3522-3539. Date of Electronic Publication: 2023 Feb 22. - Publication Year :
- 2023
-
Abstract
- The dysregulation of proteinase activity is a hallmark of osteoarthritis (OA), a disease characterized by progressive degradation of articular cartilage by catabolic proteinases such as a disintegrin and metalloproteinase with thrombospondin type I motifs-5 (ADAMTS-5). The ability to detect such activity sensitively would aid disease diagnosis and the evaluation of targeted therapies. Förster resonance energy transfer (FRET) peptide substrates can detect and monitor disease-related proteinase activity. To date, FRET probes for detecting ADAMTS-5 activity are nonselective and relatively insensitive. We describe the development of rapidly cleaved and highly selective ADAMTS-5 FRET peptide substrates through in silico docking and combinatorial chemistry. The lead substrates 3 and 26 showed higher overall cleavage rates (∼3-4-fold) and catalytic efficiencies (∼1.5-2-fold) compared to the best current ADAMTS-5 substrate ortho -aminobenzoyl(Abz)-TESE↓SRGAIY- N -3-[2,4-dinitrophenyl]-l-2,3-diaminopropionyl(Dpa)-KK-NH <subscript>2</subscript> . They exhibited high selectivity for ADAMTS-5 over ADAMTS-4 (∼13-16-fold), MMP-2 (∼8-10-fold), and MMP-9 (∼548-2561-fold) and detected low nanomolar concentrations of ADAMTS-5.
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 66
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 36891740
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.2c02090