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Dipeptide Inhibitors of Thermolysin and Angiotensin I-Converting Enzyme

[ Vol. 12 , Issue. 16 ]


Mahmud Tareq Hassan Khan, Kenichi Dedachi, Toshiro Matsui, Noriyuki Kurita, Monica Borgatti, Roberto Gambari and Ingebrigt Sylte   Pages 1748 - 1762 ( 15 )


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.


Inhibition of Zn-metalloproteinases, thermolysin, angiotensin I-converting enzyme, drug targets, inhibitors, drug discovery, antibacterial drugs, electrophoretic mobility shift assays


Center for Pharmaceutical Biotechnology (MC 870), College of Pharmacy, University of Illinois at Chicago, Molecular Biology Research Building, 900 South Ashland Avenue, Room 3100, Chicago, IL 60607-7173, USA.

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