Synthesis and evaluation of new elastase substrates as tripartate prodrugs.
Compounds consisting of a peptide sequence, 4-aminobutyric acid or 5-aminovaleric acid, respectively, as spacer units, and benzyl alcohol as a model leaving group have been prepared and tested for their ability to serve as substrates for porcine pancreatic elastase and human polymorphnuclear elastase. Those compounds containing an Ala-Ala-Ala sequence served as effective substrates for both enzymes. Hydrolytic cleavage, however, occurred exclusively at the ester bond, not at the peptide-spacer bond. In order to direct the cleavage site from the ester to the amide bond the peptide sequence was varied. We introduced a proline residue in P(3) (in relation to the ester bond) which is known to prevent the cleavage of a substrate by elastase. No hydrolysis, however, either of the ester bond or of the peptide-spacer bond, was found for these compounds.
Institute of Pharmacy, Ernst-Moritz-Arndt University, Greifswald, Germany. achilles@mail.uni-greifswald.de
Karin
K
Achilles
D000595:Amino Acid Sequence; D000818:Animals; D006801:Humans; D066298:In Vitro Techniques; D019272:Leukocyte Elastase / Q000378:metabolism; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D010196:Pancreatic Elastase / Q000378:metabolism*; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D013379:Substrate Specificity; D013552:Swine
D009842:Oligopeptides; D011355:Prodrugs; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase