Role of structural properties of bioactive peptides in their stability during simulated gastrointestinal digestion: A systematic review

The biological activities of food-derived bioactive peptides (BAPs) depend on their specific structural properties. BAP structures may be altered in the gastrointestinal tract, resulting in poor in vivo translatability of in vitro bioactivity. Structure-biostability relationship of BAPs is not well understood. Thus, this systematic review investigated all eligible studies reporting peptide sequences during in vitro digestion to determine structural properties associated with biostability. Using PRISMA guidelines, a systematic search was performed in MEDLINE and SCOPUS from the date of inception to August 2020 for studies (1) investigating isolated peptides with <12 amino acid residues; (2) using two-phase in vitro digestion models simulating a gastric digestion phase and a subsequent intestinal phase; and (3) reporting the amino acid sequences of all major peptides detected before and after simulated gastrointestinal digestion using reverse-phase high performance liquid chromatography and tandem mass spectrometry. Thirty-one articles were eligible for inclusion in the systematic review, including 27 stable and 66 unstable peptide sequences with 134 mapped cleavage sites. This study demonstrated that peptides resistant to in vitro gastrointestinal digestion have lower molecular size and hydrophobicity, more positive net charge at intestinal pH, branched-chain aliphatic N-terminal residues, the absence of C-terminal leucine, higher histidine content, and higher proline, especially at the C-terminal, compared to unstable peptides. These findings provide important guidelines for the selection and rational design of BAPs with conserved structure and therapeutic activity in vivo . • Bioactive peptides can be stable or unstable to gastrointestinal proteases. • Structural biostability of food peptides depends on their structural properties. • Chain length, size, hydrophobicity and cationic charge are major biostability determinants. • Branched-chain aliphatic N-terminal residues, histidine and proline are also important. • Findings provide important guidelines for selecting and designing biostable peptides.