Solid Phase Combinatorial Library of Phosphinic Peptides for Discovery of Matrix Metalloproteinase Inhibitors
| Autor: | Christine Bruun Schiødt, Christian Krog-Jensen, Jens Buchardt, Morten Meldal, Niels T. Foged, Jean-Marie Delaissé |
|---|---|
| Rok vydání: | 2000 |
| Předmět: |
chemistry.chemical_classification
Dipeptide Phosphines Chemistry Matrix metalloproteinase inhibitor Stereochemistry Peptide General Chemistry Combinatorial chemistry Matrix Metalloproteinases Amino acid chemistry.chemical_compound Enzyme Microscopy Fluorescence Spectrometry Mass Matrix-Assisted Laser Desorption-Ionization Phase (matter) Consensus sequence Combinatorial Chemistry Techniques Protease Inhibitors Statistical analysis Amino Acid Sequence Peptides |
| Zdroj: | Journal of Combinatorial Chemistry. 2:624-638 |
| ISSN: | 1520-4774 1520-4766 |
| DOI: | 10.1021/cc000031q |
| Popis: | A solid phase combinatorial library of 165,000 phosphinic peptide inhibitors was prepared and screened for activity against MMP-12. The inhibitors of the library had the structure XXX-Gpsi(PO2H-CH2)L-XXX, in which X is an arbitrary amino acid and Gpsi(PO2H-CH2)L is a Gly-Leu phosphinic dipeptide analogue. The library was constructed as a one-bead-two-compounds library so that every bead contained a common quenched fluorogenic substrate and a different putative inhibitor. In addition, the inhibitor part was prepared by ladder synthesis. After incubation with MMP-12, beads containing active inhibitors were selected, and the inhibitor sequences were recorded using MALDI-TOF MS. Statistical analysis of the sequences obtained from 86 beads gave rise to a consensus sequence which was resynthesized along with 20 related sequences. Three truncated sequences and 16 sequences originally present on beads were also resynthesized. The inhibitors were investigated in an enzyme kinetic assay with MMP-12 showing that the compounds derived from the consensus sequence were strong inhibitors with Ki values down to 6 nM, whereas the sequences originally present on beads varied in potency with Ki values from micromolar to nanomolar. Truncated sequences derived from the consensus sequence were poor inhibitors of MMP-12. |
| Databáze: | OpenAIRE |
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