New Perspective in Peptide Chemistry by N-Alkylation
Oral bioavailability is a major concern in the development of peptide based drugs. Peptides usually possess high selectivity and potency but the major drawback in their development as a drug is the extremely low oral availability. Insufficient bioavailability of peptides is caused by low membrane permeation, low uptake via tight junctions (paracellular transport), and active export into the gut and/or low resistance against enzymatic degradation. To circumvent these undesired properties, we envisioned the approach of multiple N-methylation. We were inspired by the cyclic peptide drug Cyclosporin which is administered orally and has seven of its eleven amide bonds N-methylated, and it violates all of the Lipinski's rules , for governing oral availability. Mono N-methylation has been employed over the years to improve lipophilicity, bioavailability, proteolytic stability and activity of peptides . However, to our knowledge multiple N-methylation has never been...
KeywordsOral Bioavailability Cyclic Peptide Metabolic Stability Paracellular Transport Oral Availability
We gratefully acknowledge the Humboldt Foundation for the support via the Max-Planck Forschungspreis. This work was also in part supported by the German Israel Foundation (GIF) and the Center of Integrated Protein Science Munich.