New Perspective in Peptide Chemistry by N-Alkylation
New Perspective in Peptide Chemistry by N-Alkylation
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DOI：
10.1007/978-0-387-73657-0_106
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发表时间：
2009-01-01
期刊：
影响因子：
--
通讯作者：
Mierke, Dale F.
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文献类型：
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作者：
Kessler, Horst;Chatterjee, Jayanta;Mierke, Dale F.
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 governing oral availability. Mono N-methylation has been employed over the years to improve lipophilicity, bioavailability, proteolytic stability and activity of peptides [2]. However, to our knowledge multiple N-methylation has never been reported, which could be owing to the availability of N-methylated amino acids, difficult coupling sequences [3], and unpredictable conformational change. Thus, our lab focused in understanding the biophysical characteristics like: conformational behavior and membrane permeability conferred by multiple N-methylation to cyclic peptides. At the same time we were also interested in developing potent analogues of Somatostatin, MTII and αIIbβ3 integrin by multiple N-methylation which would posses oral bioavailability.
