26 Aug Software assisted analysis for peptide catabolism

Anna Escolà (1,2), Antoni Riera(1,2), Aurora Valeri (3), Ismael Zamora(4,5), Tatiana Radchenko(4,5)

1. Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain; 2. Department de Química Inorgánica i Orgánica, Universitat de Barcelona, Barcelona, Spain; 3. Molecular Horizon S.R.L, Perugia, Italy;4. Pompeu Fabra University, Barcelona Spain; 5. Lead Molecular Design, S.L, Sant Cugat del Vallés, Spain

 

The interest in using peptide molecules as therapeutic agents is due to their high selectivity and efficacy. However, most peptide-derived drugs cannot be administered orally because of their instability in the gastrointestinal tract. To achieve better ADME properties the following chemical modifications are typically applied: substitution of the common L-amino acids to D-amino acids, cyclization of the peptide and others. Somatostatin or Somatotropin release-inhibiting factor (SRIF14) is a natural hormone that is being used as gastric anti-secretory drug as well as to treat growth hormone secretion disorders and endocrine tumors. The substitution of phenylalanine, using non-natural aromatic amino acids to enhance the aromatic interactions, naturally present in the hormone between Phe6, Phe7 and Phe11 has been studied before.

We used a new approach implemented in Mass-MetaSite and WebMetabase to process DDA LC-HRMS analytical data collected for a set of eight peptide drugs (somatostatin and seven synthetic analogue, containing non-standard amino acids) incubated with human serum. The effect of small chemical/monomer changes in the peptide structure with respect to the matrix catalyzed activity for serum was investigated in his peptide set. During the metabolite identification study in total 17 metabolites were found resulting in 8 distinct cleavage sites. We compared the percent of remaining parent peptide with respect to the time for all investigated peptides to compute the half-life for each case. All compounds from the dataset were hydrolyzed with the different velocity. The most stable compound was the one where Phe7 was replaced to Msa7, Trp8 to D-Trp8 and both Cys3 and Cys14 were replaced to D-Cys. It was digested significantly slower than somatostatin.