Unnatural amino acid side chains as S1, S1', and S2' probes yield cationic antimicrobial peptides with stability toward chymotryptic degradation.
This work describes how the systematic incorporation of a range of unnatural amino acid derivatives in the P1, P1', and P2' positions allows for the generation of short lactoferricin based cationic antimicrobial peptides with a stability toward chymotryptic degradation. The necessary pharmacophore sets the peptides up for degradation by chymotrypsin, and a heavily truncated native tripeptide was rapidly digested despite its short sequence. Degradation studies indicated that increased half-lives could be obtained by altering the binding to each subsite surrounding the active site without sacrificing the antimicrobial activity. Important structural and mechanistic features were revealed in a fashion not feasible through the use of native peptide substrates. The results, which are generally applicable to a range of relevant peptides, further show that not only the S1 pocket, but also to the notably less studied S1' site can be used to control the proteolytic stability by incorporating different analogues of tryptophan and arginine.
Karstad
Rasmus
R
Department of Chemistry, University of Tromsø, N-9037 Tromsø, Norway.
Isaksen
Geir
G
Brandsdal
Bjørn-Olav
BO
Svendsen
John Sigurd
JS
Svenson
Johan
J
D000596:Amino Acids / Q000138:chemical synthesis* / Q000737:chemistry; D023181:Antimicrobial Cationic Peptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002151:Calorimetry; D002918:Chymotrypsin / Q000737:chemistry*; D004355:Drug Stability; D004926:Escherichia coli / Q000187:drug effects; D006461:Hemolysis; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D013211:Staphylococcus aureus / Q000187:drug effects; D013329:Structure-Activity Relationship; D013816:Thermodynamics
D000596:Amino Acids; D023181:Antimicrobial Cationic Peptides; D009842:Oligopeptides; D002918:Chymotrypsin