title: Dipeptide inhibitors of thermolysin and angiotensin I-converting enzyme.
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.
authors.affiliation: Medical Pharmacology and Toxicology, Department of Medical Biology, Faculty of Health Sciences, University of Tromsø, 9037 Tromsø, Norway. mthkhan@uic.edu
authors.forename: Mahmud Tareq Hassan
authors.initials: MT
authors.lastname: Khan
authors.forename: Kenichi
authors.initials: K
authors.lastname: Dedachi
authors.forename: Toshiro
authors.initials: T
authors.lastname: Matsui
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Kurita
authors.forename: Monica
authors.initials: M
authors.lastname: Borgatti
authors.forename: Roberto
authors.initials: R
authors.lastname: Gambari
authors.forename: Ingebrigt
authors.initials: I
authors.lastname: Sylte
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D004151:Dipeptides / Q000494:pharmacology*; D024202:Electrophoretic Mobility Shift Assay; D008958:Models, Molecular; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D055672:Static Electricity; D013820:Thermolysin / Q000037:antagonists & inhibitors*
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D004151:Dipeptides; D007703:Peptidyl-Dipeptidase A; D013820:Thermolysin