Novel peptide inhibitors of human secretory phospholipase A2 with antiinflammatory activity

Solution structure and molecular modeling

Maung Maung Thwin, Seetharama D. Satyanarayanajois, Latha M. Nagarajarao, Kazuki Sato, Pachiappan Arjunan, Satish L. Ramapatna, Prem V. Kumar, Ponnampalam Gopalakrishnakone

Research output: Contribution to journalArticle

16 Citations (Scopus)

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 IC 50 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.

Original languageEnglish (US)
Pages (from-to)5938-5950
Number of pages13
JournalJournal of Medicinal Chemistry
Volume50
Issue number24
DOIs
StatePublished - Nov 29 2007
Externally publishedYes

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Secretory Phospholipase A2
Molecular Structure
Anti-Inflammatory Agents
Peptides
Rheumatoid Arthritis
Interleukin-1
Magnetic Resonance Spectroscopy
Fibroblasts
Escherichia coli
Messenger RNA
Enzymes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Thwin, M. M., Satyanarayanajois, S. D., Nagarajarao, L. M., Sato, K., Arjunan, P., Ramapatna, S. L., ... Gopalakrishnakone, P. (2007). Novel peptide inhibitors of human secretory phospholipase A2 with antiinflammatory activity: Solution structure and molecular modeling. Journal of Medicinal Chemistry, 50(24), 5938-5950. https://doi.org/10.1021/jm070385x

Novel peptide inhibitors of human secretory phospholipase A2 with antiinflammatory activity : Solution structure and molecular modeling. / Thwin, Maung Maung; Satyanarayanajois, Seetharama D.; Nagarajarao, Latha M.; Sato, Kazuki; Arjunan, Pachiappan; Ramapatna, Satish L.; Kumar, Prem V.; Gopalakrishnakone, Ponnampalam.

In: Journal of Medicinal Chemistry, Vol. 50, No. 24, 29.11.2007, p. 5938-5950.

Research output: Contribution to journalArticle

Thwin, MM, Satyanarayanajois, SD, Nagarajarao, LM, Sato, K, Arjunan, P, Ramapatna, SL, Kumar, PV & Gopalakrishnakone, P 2007, 'Novel peptide inhibitors of human secretory phospholipase A2 with antiinflammatory activity: Solution structure and molecular modeling', Journal of Medicinal Chemistry, vol. 50, no. 24, pp. 5938-5950. https://doi.org/10.1021/jm070385x
Thwin, Maung Maung ; Satyanarayanajois, Seetharama D. ; Nagarajarao, Latha M. ; Sato, Kazuki ; Arjunan, Pachiappan ; Ramapatna, Satish L. ; Kumar, Prem V. ; Gopalakrishnakone, Ponnampalam. / Novel peptide inhibitors of human secretory phospholipase A2 with antiinflammatory activity : Solution structure and molecular modeling. In: Journal of Medicinal Chemistry. 2007 ; Vol. 50, No. 24. pp. 5938-5950.
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