Development of Selective ADAMTS-5 Peptide Substrates to Monitor Proteinase Activity.
J Med Chem
; 66(5): 3522-3539, 2023 03 09.
Article
em En
| MEDLINE
| ID: mdl-36891740
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 (â¼3-4-fold) and catalytic efficiencies (â¼1.5-2-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-NH2. They exhibited high selectivity for ADAMTS-5 over ADAMTS-4 (â¼13-16-fold), MMP-2 (â¼8-10-fold), and MMP-9 (â¼548-2561-fold) and detected low nanomolar concentrations of ADAMTS-5.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Osteoartrite
/
Cartilagem Articular
Limite:
Humans
Idioma:
En
Revista:
J Med Chem
Ano de publicação:
2023
Tipo de documento:
Article