ISSN:
1573-904X
Keywords:
N-glyoxylyl-des-glyl-pexiganan
;
piperazinedionyl-des-glyl-pexiganan
;
N-glyoxylyl-peptides
;
N-terminal oxidation of peptides in drug formulation
Source:
Springer Online Journal Archives 1860-2000
Topics:
Chemistry and Pharmacology
Notes:
Abstract Purpose. The purpose of this study was to identify four majordegradation products, which were formed during a stress study of pexiganan(a 22-mer peptide) in a 1% formulation. Methods. The degradation products were isolated and characterizedby LC/MS, tryptic and aminopeptidase digests. Results. One of the degradation products was shown to bedes-glyl-pexiganan. The other three are structural isomers ofN-glyoxylyl-des-glyl-pexiganan. These isomers undergo reversible inter-conversions,as well as decompose irreversibly to des-glyl-pexiganan. Thus, all theimpurities were formed from a single oxidation product of pexiganan,N-glyoxylyl-des-glyl-pexiganan. The aldehyde group of the glyoxylylresidue and the NH-amide of the adjacent isoleucine residue form apiperazinedione derivative of des-glyl-pexiganan. This heterocycliccompound rearranges to other tautomers or back to the N-glyoxylylcompound (see Fig. 3). Tryptic digests of the three degradation productsshowed that their N-terminal segment produced N-glyoxylyl-I-G-Kwhereas the N-terminal segment of pexiganan produced G-I-G-K. Allthe other tryptic-digest segments were identical to those formed inpexiganan. The LC/MS of the N-terminal segment and of syntheticN-glyoxylyl-I-G-K were identical. The enzymatic resistance of the threeimpurities to undergo aminopeptidase-M cleavage further supportedthe conclusion that their N-terminal amino residues are substituted. Conclusions. After a year under stress conditions 1% pexiganan creamlost about 15% of the active component to oxidative-deamination,where the N-terminal glycine residue was oxidized toN-glyoxylyl-des-glyl-pexiganan. The other nine ε-amino lysine-residues of the peptidestayed intact. This oxidation product inter-converted and formed twoadditional impurities, tautomers ofpiperazinedionyl-des-glyl-pexiganan, and decomposed todes-glyl-pexiganan, the forth impurity.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1023/A:1007521515109
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