J Med Chem. 2007 Nov 29;50(24):5938-50. Epub 2007 Nov 1.

Novel peptide inhibitors of human secretory phospholipase A2 with antiinflammatory activity: solution structure and molecular modeling.

Thwin MM, Satyanarayanajois SD, Nagarajarao LM, Sato K, Arjunan P, Ramapatna SL, Kumar PV, Gopalakrishnakone P.

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Department of Anatomy, Yong Loo Lin School of Medicine, 4 Medical Drive, National University of Singapore, Singapore 117597.

Abstract

Secretory phospholipase A2 (sPLA2) and matrix metallopreoteinases (MMPs) are key enzymes involved in rheumatoid arthritis (RA), and their modulation thus represents a potential therapeutic option. On the basis of Escherichia coli radioassay, synthetic peptides were designed and screened for sPLA2 inhibition. The linear peptide, 10f (PIP-18), inhibited the recombinant human synovial sPLA2 activity with an IC50 of 1.19 microM. Not only did the peptide interfere with the function of sPLA2, but it also appeared to inhibit mRNA expression of sPLA2 and various MMPs in IL-1beta-stimulated RA synovial fibroblast (RASF) cultures and thereby the production of the corresponding proteins (>80% inhibition). Nuclear magnetic resonance (NMR), modeling, and docking studies indicate that in solution the peptide exhibits a beta-turn at residues Trp-Asp-Gly-Val and possibly binds to the hydrophobic channel of sPLA2. The results strongly suggest that the modulatory action of peptide 10f may play a major role in counteracting the development of RA.

PMID:: 17973469; [PubMed - indexed for MEDLINE]

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Structures reported by this article

Spla2 Inhibitor Pip 17

PDB: 2P5J

Source: synthetic construct

Method: Solution Nmr

See all 2 structures...

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