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In vitro ADMET and physicochemical investigations of poly-N-methylated peptides designed to inhibit Aβ aggregation
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
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2010 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 18, no 16, 5896-5902 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2010. Vol. 18, no 16, 5896-5902 p.
Keyword [en]
Alzheimer's disease, Amyloid beta peptide, N-Methylated peptide, ADMET
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-132386DOI: 10.1016/j.bmc.2010.06.087ISI: 000280664100012PubMedID: 20659803OAI: oai:DiVA.org:uu-132386DiVA: diva2:357722
Available from: 2010-10-19 Created: 2010-10-19 Last updated: 2017-12-12Bibliographically approved

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