Two things make a peptide orally active. The first is protection against gastrointestinal proteases: gut peptidases cleave linear peptides at recognisable amino-acid sequences, so peptides with cyclic structures, non-natural amino acids, chemical protection at the termini, or unusual bond arrangements can survive the gut transit that would destroy a naturally-sequenced small peptide. The second is adequate absorption from the intestinal lumen into the portal circulation, which usually requires small molecular size and appropriate lipophilicity.

The peptides on this site with meaningful oral bioavailability all satisfy both conditions in a distinctive way. Noopept is a peptidomimetic — a peptide-derived molecule where the N-terminus is protected by an N-phenylacetyl group and the C-terminus by an ethyl ester, both of which resist enzymatic cleavage. Cycloprolylglycine is a small cyclic dipeptide whose ring structure resists linear-peptide-specific proteases. Dihexa is engineered with a hexanoyl-terminus and an aminohexanoic-acid amide that block the two main proteolytic attacks and additionally confer blood-brain-barrier penetration.

The engineering effort behind each of these molecules is substantial — none of them is a native peptide sequence. Oral activity in the cognitive-peptide space is nearly always the result of deliberate medicinal-chemistry work rather than accident.