All-D-Bradykinin and the Problem of Peptide Antimetabolites

Abstract

IN the past there has been much speculation about the effect of the incorporation of D-amino-acids into biologically active peptides. Several of the antibiotic peptides, as well as penicillin, contain D-amino-acids. The antibacterial activity may be associated with the presence of these D-amino-acids. In the case of the peptide hormones, where all the amino-acids are of the L series, the replacement of one amino-acid by the D isomer has usually failed to destroy the biological activity. Thus hormonal activity of bradykinin was retained when either serine¹ or one of the phenylalanines² was changed to the D-configuration. In angiotensin, inversion of arginine³, aspartic acid⁴, or phenylalanine⁵ did not destroy the biological activity, although the D-tyrosine analogue was inactive⁵. Examination of melanophore stimulating hormone (MSH)^6,7 and eledoisin⁸ has shown that the biological activity was retained when one amino-acid was changed to the D-configuration. In contrast to these data on the change of a single residue, the inversion of all the amino-acid residues in a pentapeptide which has the hormonal activity of MSH was found not only to cause loss of hormonal activity, but to produce an antimetabolite of MSH⁹. This peptide, D - histidyl - D - phenylalanyl - D - arginyl - D - tryptophylglycine, was found to antagonize the action of the corresponding all-L pentapeptide as well as that of MSH. Because we have been attempting to make specific antimetabolites of bradykinin¹⁰, and because there is as yet no general method for prediction of the structural alterations required to make antimetabolites of peptides, we have synthesized all-D-bradykinin and tested it for biological activity in an effort to find out whether the inversion of all the amino-acids of a peptide may be a generally applicable method for the synthesis of specific peptide antagonists.