Combinatorial Screening Identifies Novel Promiscuous Matrix Metalloproteinase Activities that Lead to Inhibition of the Therapeutic Target IL-13.
Chem Biol
; 22(11): 1442-1452, 2015 Nov 19.
Article
in En
| MEDLINE
| ID: mdl-26548614
ABSTRACT
The practical realization of disease modulation by catalytic degradation of a therapeutic target protein suffers from the difficulty to identify candidate proteases, or to engineer their specificity. We identified 23 measurable, specific, and new protease activities using combinatorial screening of 27 human proteases against 24 therapeutic protein targets. We investigate the cleavage of monocyte chemoattractant protein 1, interleukin-6 (IL-6), and IL-13 by matrix metalloproteinases (MMPs) and serine proteases, and demonstrate that cleavage of IL-13 leads to potent inhibition of its biological activity in vitro. MMP-8 degraded human IL-13 most efficiently in vitro and ex vivo in human IL-13 transgenic mouse bronchoalveolar lavage. Hence, MMP-8 is a therapeutic protease lead against IL-13 for inflammatory conditions whereby reported genetic and genomics data suggest an involvement of MMP-8. This work describes the first exploitation of human enzyme promiscuity for therapeutic applications, and reveals both starting points for protease-based therapies and potential new regulatory networks in inflammatory disease.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Interleukin-13
/
Matrix Metalloproteinases
Type of study:
Diagnostic_studies
/
Prognostic_studies
/
Screening_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
Chem Biol
Journal subject:
BIOLOGIA
/
BIOQUIMICA
/
QUIMICA
Year:
2015
Document type:
Article