Sequence substitutions
Enzymes recognize molecular structures, so changing particular residues can alter susceptibility to cleavage. Some design studies replace selected L-amino acids with D-amino acids. The effect depends on which residues change and on the peptide being tested; this is a research strategy, not a guarantee of useful activity. (Bruno, Miller & Lim: Basics and recent advances in peptide and protein drug delivery).
Cyclization
Cyclization creates a covalent connection that closes part or all of a peptide into a ring. It can alter flexibility and access to cleavage sites, and some cyclic molecules show improved stability or permeability. A ring does not automatically produce oral absorption or a better drug: the resulting shape must still support the desired interactions. (Bruno, Miller & Lim: Basics and recent advances in peptide and protein drug delivery).
Lipidation and albumin interactions
Lipidation attaches a lipid group. The group may promote reversible albumin binding and prolong exposure for some molecules. However, changing the lipid, linker or attachment site can alter receptor activity and solubility, so a promising mechanism must be checked against measurements for that exact design. (Menacho-Melgar and colleagues: A review of lipidation in the development of advanced protein and peptide therapeutics).
Polymer attachment and other approaches
PEGylation attaches polyethylene glycol, a polymer. Increasing effective molecular size and shielding the therapeutic can influence filtration and degradation, but reduced activity, immune responses and other limitations also need evaluation. PEGylation, lipidation and cyclization are distinct approaches and should not be treated as synonyms. (Bruno, Miller & Lim: Basics and recent advances in peptide and protein drug delivery).
A useful comparison framework
For each modification, ask four questions: What changed chemically? What property was measured? In what model was it measured? What tradeoff or uncertainty remains? Do not compare an animal permeability result with a human clinical outcome as if both were the same kind of evidence. (Bruno, Miller & Lim: Basics and recent advances in peptide and protein drug delivery).