Table 3.
Direct modifications of peptides and proteins. Overview of direct modifications made to peptides and the resulting change in bioavailability.
| Method of modification | Subtype of modification | Successfully modified compound(s) | Outcome | Ref. |
|---|---|---|---|---|
| Cyclization | CSA, somatostatin, encephalin | Reduces hydrophilicity, decreases conformational flexibility, enhances membrane permeability and increases stability to proteolysis | [8,31,32] | |
| PEG | Direct, permanent modification | Insulin, salmon calcitonin | Resistance to intestinal enzymes, slowed systemic clearance, increased intestinal absorption, decreased glucose levels (insulin) | [41,42] |
| Prodrug | IFN-B-1b | Decreased aggregation, maintained activity, dimished IgG response, 100-fold increase in AUC, improved protection from enzymatic degradation | [41,53] | |
| B12 conjugation | ε position on the corrin ring | Albumin, G-CSF, EPO, LHRH and analogues, DP3, dextran nanoparticles | Increased oral absorption via vitamin B12-intrinsic factor binding | [44] |
| 5′-hydroxy on ribose unit of the α tail | IFN, insulin | Efficacy is hindered by naturally low capacity for B12 absorption | [44] | |
| Phosphate unit of the α tail | Albumin, γG-globulin | Steric hindrance limits absorption, activity of the therapeutic | [44] | |
| Lipidization | Reversible aqueous lipidization with n-palmitoyl cysteinyl 2-pyridyl disulfide | Salmon calcitonin | AUC 19-times higher than unmodified, marker for bone resorption reduced | [45] |
| N-acetylation | Salmon calcitonin | Improved oral bioavailability, marginally improved resistance to trypsin and leucine aminopeptidase, enhanced membrane permeability | [54] | |
| D-AA | 6 out of 11 l-AA substituted for d-AA | MUC2 | Resistance to proteolytic cleavage by chymotrypsin, elastase, papain, pepsin, trypsin and carboxypeptidase | [52] |
| Prodrug | Esterification | Desmopressin | Increased permeation of Caco-2 cell layer, active in plasma after cleavage | [55] |
| Perbuytrylation | Glycovir | Increased bioavailability | [56] |
AA: Amino acid; AUC: Area under the curve; CSA: Cyclosporine; DP3: Octapeptide (Glu-Ala-Ser-Ala-Ser-Tyr-Ser-Ala); EPO: Erythropoietin; LHRH:Lutenizing hormone releasing hormone.