期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 18, 期 16, 页码 5896-5902出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2010.06.087
关键词
Alzheimer's disease; Amyloid beta peptide; N-Methylated peptide; ADMET
资金
- Foundation Olle Engkvist Byggm stare, Vetenskapsradet (The Swedish Research Council)
- Sweden-South African Research Link Grant
- Wenner-Gren foundation
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.
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