Bioactive peptides

Many dietary proteins contain short sequences that do something other than supply amino acids once they are released. They are inactive within the parent protein — “encrypted” — and are liberated by proteolysis, whether by digestion, by fermentation, or by directed enzymatic hydrolysis in a factory.

How they are produced

The industrial route is controlled hydrolysis: a protein substrate, one or more proteases chosen for their cleavage specificity, and a defined stopping point. Specificity is what matters, since the enzyme determines which bonds are cut and therefore which sequences appear. Fermentation achieves the same by microbial proteolysis, notably in aged cheese and fermented milks, where the sequences accumulate over time.

Selection has moved from screening hydrolysates to searching sequence databases computationally for motifs associated with a given activity, then producing candidates synthetically for testing. That accelerates discovery. It does not address the field’s actual bottleneck.

What is best characterised

The ACE-inhibitory peptides are the most studied. Short sequences from milk casein — the tripeptides isoleucine-proline-proline and valine-proline-proline among them — inhibit angiotensin-converting enzyme, the same target as a major class of antihypertensive drugs. Their proline content is not incidental: it makes them relatively resistant to further breakdown.

Others include caseinophosphopeptides, whose phosphorylated serine clusters bind calcium and keep it soluble in the intestine; casomorphins, opioid-receptor-active fragments of β-casein; antimicrobial peptides such as lactoferricin, released from lactoferrin by gastric pepsin; and a large set of antioxidant peptides identified by in-vitro assays.

The bioavailability problem

This is the honest centre of the subject. A peptide added to a food must survive gastric and pancreatic proteases, then cross the intestinal epithelium, and then survive in plasma long enough to reach a target.

Each step is hostile. The brush border of the small intestine is densely covered with peptidases that hydrolyse peptides during absorption, and the transporter that carries peptides efficiently, PepT1, handles only di- and tripeptides — longer peptides are largely broken down first. Whatever is absorbed then meets plasma and tissue peptidases. Plasma half-lives for such peptides are typically minutes.

The consequence is that a peptide’s potency in an in-vitro assay is a weak predictor of any effect in a person. The literature is large, dominated by in-vitro and animal work, and the human trials that exist — most extensively for ACE-inhibitory peptides and blood pressure — show effects that are small, inconsistent between studies, and subject to the publication biases that affect small-trial literatures generally. Meta-analyses in this area have reached differing conclusions depending on which trials were included.

A page on this subject should say what is defensible: the mechanisms are real and demonstrable in vitro, production is a solved problem, and translation into a measurable clinical effect through the diet is not established for most claimed activities. The exceptions worth watching are peptides that are structurally resistant to degradation, and delivery strategies that protect them — because those address the mechanism that actually limits the field.