Synthesis and antibacterial properties of peptidyl derivatives and cyclopeptides structurally based upon the inhibitory centre of human cystatin C - Dissociation of antiproteolytic and antibacterial effects

Cysteine protease-inhibiting proteins of the cystatin superfamily can inhib it the replication of certain viruses and bacteria. The inhibitory centre o f human cystatin C, the most widely distributed human cystatin, comprises t hree peptide segments. The present work describes the synthesis and antibac terial activity of 27 new peptidyl derivatives or cyclopeptides based upon the aminoterminal segment Arg(8)-Leu(9)-Val(10)-Gly(11). Fourteen of the ne w compounds displayed antibacterial activity against from 1 up to 9 of 17 c linically important bacterial species tested. Antiproteolytic activity of a compound was usually not required for its antibacterial capacity. Peptidyl diazomethanes generally had a very narrow antibacterial spectrum, inhibiti ng only Streptococcus pyogenes, whereas cyclopeptides and peptidyl derivati ves of the general structure X-Arg-Leu-NH-CH(iPr)-CH2-NH-Y had a much wider spectrum. The most potent of these substances displayed approximately equa l minimal inhibitory and bactericidal concentrations of about 20 mug/ml for both Staphylococcus aureus and S. pyogenes and were devoid of antiproteoly tic activity. Several of the new substances could protect mice against leth al intraperitoneal challenge with S. pyogenes. Though their target remains to be disclosed, the group of substances here reported might be promising f or the development of antibacterial drugs and the discovery of novel princi ples of action.