TY - JOUR
T1 - Novel peptide inhibitors of human secretory phospholipase A2 with antiinflammatory activity
T2 - Solution structure and molecular modeling
AU - Thwin, Maung Maung
AU - Satyanarayanajois, Seetharama D.
AU - Nagarajarao, Latha M.
AU - Sato, Kazuki
AU - Arjunan, Pachiappan
AU - Ramapatna, Satish L.
AU - Kumar, Prem V.
AU - Gopalakrishnakone, Ponnampalam
PY - 2007/11/29
Y1 - 2007/11/29
N2 - 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 μM. 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-1β-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 β-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.
AB - 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 μM. 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-1β-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 β-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.
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U2 - 10.1021/jm070385x
DO - 10.1021/jm070385x
M3 - Article
C2 - 17973469
AN - SCOPUS:37849012702
SN - 0022-2623
VL - 50
SP - 5938
EP - 5950
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 24
ER -