Dipeptide Inhibitors of Thermolysin and Angiotensin I-Converting Enzyme

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 of TLPs is believed to be a novel strategy in the 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 inhibit TLN induced cleavage of the transcription factor nuclear factor kappa beta (NF-kappa B) was studied by electrophoretic mobility shift assays (EMSAs). Nine peptides inhibited ACE with IC50 values in the range 0.48 (IVY) to 1408 (HF) mu M, while seven inhibited TLN with IC50 values in the range 0.00034 (IY) to 95640 (FW) mu M. Calculations indicated that the peptides occupied the S1' and S2' subsites of ACE, and that IY, LW and IW occupied the S1' and S2' subsites, while FW, WL and WV occupied the S1 and S1' subsites of TLN. EMSA showed that peptides inhibited TLN induced cleavage of NF-kappa B. The studied peptides may form as a basis for the design of new compound stargeting TLN with a potential in the treatment of bacterial infections.