Peptide prodrugs, targeting

Bai, J. P. F., pGlu-L-Dopa-Pro a tripeptider prodrug targeting the intestinal peptide transporter for absorption and tissue enzymes for conversation, Pharm. Res. 1995, 12, 1101-1104. 

A series of peptide prodrugs ofh-a-methyldopa were prepared and shown to exhibit high affinity for the peptide carrier system [32], In an in situ intestinal perfusion model, the prodrugs Phe-L-a-methyldopa (6.10) and l-a-methyldopa-Phe (6.11) showed permeabilities that were 10- and 20-times higher, respectively, than that of L-a-methyldopa. The other derivatives examined (Gly- and Pro-L-a-methyldopa, L-a-methyldopa-Pro) also had better permeabilities. These and other results indicate that the peptide transport system has a relatively low substrate specificity and can indeed be targeted by peptide prodrugs to improve absorption [33],... 

Fig. 6.9. Rationale for the design of peptidic prodrugs (6.15) of 5-fluorouracil (6.17) targeting microbial peptides permeases and peptidases [37]...

Enzyme-Mediated, Tissue-Selective Targeting of Peptide Prodrugs... 

Hoen P.A. C., Prince P., Van der Bilt E., Valentijn A. R., Meeuwenoord N.J., Princen H., Bijsterbosch M.K., van der Marel G.A., van Boom J.H., van BerkelT.J.C. Design of a targeted peptide nucleic acid prodrug to inhibit hepatic human microsomal triglyceride transfer protein expression in hepato-cytes. Bioconjug. Chem. 2002 13 295-302. 

Owing to their particular chemical structure, amide prodrugs can be designed for targeting peptide and nutrient transporters to enhance permeability. In this application, amide prodrugs are also shown to generally... 

The ileal bile acid transporter (IBAT) transports conjugated bile acids in a Na + -dependent manner. Like the peptide transporter, it serves as a target for prodrugs, which consist of drugs being coupled to the hydroxyl group at position 3 of the steroid ring system of a bile acid [25, 26]. 

Perkins EJ, Abraham T (2007) Pharmacokinetics, metabolism, and excretion of the intestinal peptide transporter 1 (SLC15Al)-targeted prodrug (IS, 2S, 5R, 6S)-2-[(2 S)-(2-amino)propionyl]aminobicyclo[3.1.0.]hexen-2, 6-di carboxylic acid (LY544344) in rats and dogs assessment of first-pass bioactivation and dose linearity. Drug Metab Dispos 35 1903-1909... 

---