Dipeptide inhibitors of thermolysin and angiotensin I-converting enzyme

Mahmud Tareq Hassan Khan, Kenichi Dedachi, Toshiro Matsui, Noriyuki Kurita, Monica Borgatti, Roberto Gambari, Ingebrigt Sylte

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Thermolysin (TLN) and other thermolysin-like zinc metalloproteinases (TLPs),are important virulence factors for pathogenesis of bacterial infections by suppressing the innate immune system of the host. Therapeutic inhibition ofTLPs is believed to be a novel strategy inthe development of a new generation antibiotics.In the present study inhibition of TLN and angiotensin I-converting enzyme (ACE) by small peptides were studied by in vitro binding assays and theoretical calculations. The capacity of the peptides to inhibitTLN induced cleavage ofthe transcription factor nuclear factor kappa beta (NF-κB) was studied by electrophoretic mobility shift assays (EMSAs).Nine peptides inhibited ACE with IC50 values in the range 0.48 (IVY) to 1408 (HF) μM, while seven inhibited TLN with IC50 values in the range 0.00034 (IY) to 95640 (FW) μM. Calculations indicated that the peptides occupied the S1' and S2' subsites of ACE, and that IY, LW and IW occupiedthe S1' and S2' subsites, while FW, WL and WV occupiedthe S1 and S1' subsites of TLN. EMSA showed that peptides inhibited TLN induced cleavage of NF-κB. The studied peptides may form as a basis for the design of new compoundstargeting TLN with a potential in the treatment of bacterial infections.

Original languageEnglish
Pages (from-to)1748-1762
Number of pages15
JournalCurrent Topics in Medicinal Chemistry
Volume12
Issue number16
DOIs
Publication statusPublished - Dec 1 2012

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Thermolysin
Dipeptides
Angiotensin-Converting Enzyme Inhibitors
Peptides
Peptidyl-Dipeptidase A
Electrophoretic Mobility Shift Assay
Bacterial Infections
Inhibitory Concentration 50
Metalloproteases
Virulence Factors
Zinc
Immune System
Transcription Factors
Anti-Bacterial Agents

All Science Journal Classification (ASJC) codes

  • Drug Discovery

Cite this

Khan, M. T. H., Dedachi, K., Matsui, T., Kurita, N., Borgatti, M., Gambari, R., & Sylte, I. (2012). Dipeptide inhibitors of thermolysin and angiotensin I-converting enzyme. Current Topics in Medicinal Chemistry, 12(16), 1748-1762. https://doi.org/10.2174/156802612803989246

Dipeptide inhibitors of thermolysin and angiotensin I-converting enzyme. / Khan, Mahmud Tareq Hassan; Dedachi, Kenichi; Matsui, Toshiro; Kurita, Noriyuki; Borgatti, Monica; Gambari, Roberto; Sylte, Ingebrigt.

In: Current Topics in Medicinal Chemistry, Vol. 12, No. 16, 01.12.2012, p. 1748-1762.

Research output: Contribution to journalArticle

Khan, MTH, Dedachi, K, Matsui, T, Kurita, N, Borgatti, M, Gambari, R & Sylte, I 2012, 'Dipeptide inhibitors of thermolysin and angiotensin I-converting enzyme', Current Topics in Medicinal Chemistry, vol. 12, no. 16, pp. 1748-1762. https://doi.org/10.2174/156802612803989246
Khan, Mahmud Tareq Hassan ; Dedachi, Kenichi ; Matsui, Toshiro ; Kurita, Noriyuki ; Borgatti, Monica ; Gambari, Roberto ; Sylte, Ingebrigt. / Dipeptide inhibitors of thermolysin and angiotensin I-converting enzyme. In: Current Topics in Medicinal Chemistry. 2012 ; Vol. 12, No. 16. pp. 1748-1762.
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