Proceedings book download - 5Z.com

Proceedings of the 31 st European Peptide SymposiumMichal Lebl, Morten Meldal, Knud J. Jensen, Thomas Hoeg-Jensen (Editors)European Peptide Society, 2010Structure–Activity Relationship Studies for Cystapep 1and Its AnaloguesAneta Pogorzelska 1 , Sylwia Rodziewicz-Motowidło 1 ,Maria Smużyńska 1 , Zet Freiburghaus 2 , Anders Grubb 2 ,and Franciszek Kasprzykowski 11 Department of Medicinal Chemistry, University of Gdansk, Gdansk, 80-952, Poland;2 Department of Clinical Chemistry, University Hospital, Lund, SE-221 85, SwedenIntroductionIn 1989, a group of potential antimicrobial compounds structurally based upon the aminoterminalinhibitory centre of human cystatin C was described. Peptidyl diazomethanes werefound to inhibit growth of Streptococcus pyogenes. Because of their origin it was thoughtthat this sequence inhibits cysteine protease produced by bacteria, but subsequent analysisof a number of similar compounds showed that their antimicrobial effect does not includeprotease inhibition. The search for both linear and cyclic analogues found that one of thecompounds, called later Cystapep 1 (CpV) (Figure 1), has comparatively low MIC andMBC values for S. pyogenes and S. aureus. Cystapep 1 is also effective against antibioticresistant staphylococci and streptococci, as well as against susceptible strains of thesespecies [1,2].Results and DiscussionCalorimetric traces of interaction between CpV analogues and POPG LUVs were measuredby ITC experiments. Binding parameters were defined on the assumption that all surface ofLUVs is available for interaction and to disregard the electrostatic attraction. In the case ofinactive analogues A-89 and A-92 the research showed that they do not interact with POPGLUVs. Among others, compounds A-134 and CpV areN H 2NHNHOONHFig. 1. Cystapep 1 structure.ONHOONHNHactive against gram-positive bacteria whilst A-141 does notinhibit growth of tested pathogens, however, the exothermicbinding reactions are observed for these peptidomimetics.Under the condition used, the peptidomimetics arecompletely bound to the lipid vesicles. In the case ofCystapep 1 complicated titration pattern is observed. Theheat of reaction did not decrease smoothly with eachinjection but showed an inflection point. This behaviourwas observed previously for some surfactant and wasexplained by a process which could be identified as amicelle formation demicellization equilibrium of thephospholipid / surfactant mixture [3].Fig. 2. Superimposed conformations of studied peptidyl derivatives.260