Chatterjee, Urmimala
- Department of Animal Biosciences, Swedish University of Agricultural Sciences
Abstract
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 A beta-peptide, pathological hallmark of Alzheimer's disease (AD), have previously been shown to inhibit aggregation of A beta 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. (C) 2010 Elsevier Ltd. All rights reserved.
Keywords
Alzheimer's disease; Amyloid beta peptide; N-Methylated peptide; ADMET
Published in
Bioorganic and Medicinal Chemistry
2010, volume: 18, number: 16, pages: 5896-5902
Publisher: PERGAMON-ELSEVIER SCIENCE LTD
SLU Authors
Johansson, Jan
- Department of Animal Biosciences, Swedish University of Agricultural Sciences
- Department of Animal Biosciences, Swedish University of Agricultural Sciences
UKÄ Subject classification
Molecular Biology
Biochemistry
Publication identifier
- DOI: https://doi.org/10.1016/j.bmc.2010.06.087
Permanent link to this page (URI)
https://res.slu.se/id/publ/48042