Design and synthesis of β-strand-fixed peptides inhibiting aggregation of amyloid β-protein. Issue 18 (15th September 2020)

• Record Type: Journal Article
• Authors: Tanaka, Fumiya; Shibata, Kana; Monobe, Yoko; Akagi, Ken-ichi; Masuda, Yuichi
• Is Part Of: Bioorganic & medicinal chemistry. Volume 28:Issue 18(2020)
• Publication Date: 2020-09-15
• Subjects: Amyloid β-protein -- β-Sheet breaker peptide -- β-Strand mimetics -- Conformation fixation -- Conformation analysis; AD Alzheimer's disease -- Aβ amyloid β-proteins -- BSBp β-sheet breaker peptide -- BBB blood-brain barrier -- Tyr(Allyl) O-allyl-tyrosine -- Gly(Allyl) allylglycine -- BSFp β-strand-fixed peptides -- HBTU [Bis(dimethylamino)methylene]-1H-benzotriazolium 3-Oxide Hexafluorophosphate -- DIEA N, N-diisopropylethylamine -- RCM ring-closing metathesis -- DMSO dimethyl sulfoxide -- NOE nuclear Overhauser effect -- Th-T thioflavin-T, TEM, transmission electron microscopy -- MTT 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide -- RP-HPLC reversed-phase high performance liquid chromatography -- HFIP 1, 1, 1, 3, 3, 3-hexafluoro-2-propanol -- PBS phosphate buffered saline; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2020.115676
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: Aggregation of 42-residue amyloid β-protein (Aβ42) can be prevented by β-sheet breaker peptides (BSBps) homologous to LVFFA residues, which are included in a β-sheet region of Aβ42 aggregates. To enhance the affinity of BSBps to the Aβ42 aggregates, we designed and synthesized β-strand-fixed peptides (BSFps) whose side chains were cross-linked by ring closing metathesis. Conformation analysis verified that the designed peptides could be fixed in β-strand conformation. Among the synthesized pentapeptides, 1 and 12, whose side chains of 2nd and 4th residues were cross-linked, significantly inhibited the aggregation of Aβ42. This suggested that β-strand-fixation of BSBps could enhance their inhibitory activity against the Aβ42 aggregation. However, pentapeptides 1 and 12 had little effect on morphology of Aβ42 aggregates (fibrils) and neurotoxicity of Aβ42 against SH-SY5Y cells.