Send to

Choose Destination
Bioorg Med Chem. 2010 Aug 15;18(16):5896-902. doi: 10.1016/j.bmc.2010.06.087. Epub 2010 Jul 1.

In vitro ADMET and physicochemical investigations of poly-N-methylated peptides designed to inhibit Abeta aggregation.

Author information

Department of Biochemistry & Organic Chemistry, Uppsala University, Uppsala, Sweden.


N-Methylation is a common strategy for improving oral bioavailability of peptide-based lead structures. Herein, we present a detailed study on how the degree of N-methylation affects the absorption-distribution-metabolism-excretion-toxicity (ADMET) properties such as solubility, membrane transport, proteolytic stability, and general cell toxicity of the investigated peptides. As representative structures we chose hexapeptides 1-8. These peptides, corresponding to N-methylated analogues of residues 16-21 and 32-37 of the Abeta-peptide, pathological hallmark of Alzheimer's disease (AD), have previously been shown to inhibit aggregation of Abeta fibrils in vitro. This study suggests that poly-N-methylated peptides are non-toxic and have enhanced proteolytic stability over their non-methylated analogues. Furthermore, solubility in aqueous solution is seen to increase with increased degree of N-methylation, while membrane transport was found to be low for all investigated hexapeptides. The present results, together with those reported in the literature, suggest that poly-N-methylated peptides, especially shorter or equal to six residues, can be suitable candidates for drug design.

[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center