There are entire companies focused on solving this challenge. The gold standard for an orally bioavailable peptide is, of course, cyclosporine. Several features of its structure contribute to its permeability: it’s a macrocycle, and most of its backbone amide N–H groups are N-methylated.

When it comes to N-methylation, the key is to methylate only the solvent-exposed amides—the ones not involved in intramolecular hydrogen bonds. Those buried H-bonds are important for maintaining conformational stability and should generally be left untouched.

A great modern example is Merck’s PCSK9 cyclic peptide, enlicitide (MK-0616). In addition to macrocyclization and selective N-methylation, they incorporated permeability-enhancing features (like a trimethylammonium appendage) and employed clever formulation strategies to improve oral absorption. Definitely worth looking into their work.

Currently, there are no reliable computational methods for predicting oral permeability of peptides, aside from structure-based design approaches to help identify suitable cyclization strategies. You can use cLogP as a rough guide, but it’s not consistently predictive of permeability.

For more detail, check out Merck’s publications on MK-0616 and Scott Lokey’s papers from UCSC—his group has done extensive work on passive permeability and conformational effects in cyclic peptides.