title: In vitro ADMET and physicochemical investigations of poly-N-methylated peptides designed to inhibit Abeta aggregation.
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 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.
authors.affiliation: Department of Biochemistry & Organic Chemistry, Uppsala University, Uppsala, Sweden.
authors.forename: Partha Pratim
authors.initials: PP
authors.lastname: Bose
authors.forename: Urmimala
authors.initials: U
authors.lastname: Chatterjee
authors.forename: Ina
authors.initials: I
authors.lastname: Hubatsch
authors.forename: Per
authors.initials: P
authors.lastname: Artursson
authors.forename: Thavendran
authors.initials: T
authors.lastname: Govender
authors.forename: Hendrik G
authors.initials: HG
authors.lastname: Kruger
authors.forename: Margareta
authors.initials: M
authors.lastname: Bergh
authors.forename: Jan
authors.initials: J
authors.lastname: Johansson
authors.forename: Per I
authors.initials: PI
authors.lastname: Arvidsson
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors*; D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D008745:Methylation; D016716:PC12 Cells; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D055550:Protein Stability; D051381:Rats; D012995:Solubility
chemical_list: D016229:Amyloid beta-Peptides; D010455:Peptides