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000162730 0247_ $$2doi$$a10.1002/cbic.202100287
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000162730 037__ $$aDZNE-2021-01387
000162730 041__ $$aEnglish
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000162730 1001_ $$aMalhis, Marwa$$b0
000162730 245__ $$aPotent Tau Aggregation Inhibitor D-Peptides Selected against Tau-Repeat 2 Using Mirror Image Phage Display.
000162730 260__ $$aWeinheim$$bWiley-VCH$$c2021
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000162730 520__ $$aAlzheimer's disease and other Tauopathies are associated with neurofibrillary tangles composed of Tau protein, as well as toxic Tau oligomers. Therefore, inhibitors of pathological Tau aggregation are potentially useful candidates for future therapies targeting Tauopathies. Two hexapeptides within Tau, designated PHF6* (275-VQIINK-280) and PHF6 (306-VQIVYK-311), are known to promote Tau aggregation. Recently, the PHF6* segment has been described as the more potent driver of Tau aggregation. We therefore employed mirror-image phage display with a large peptide library to identify PHF6* fibril binding peptides consisting of D-enantiomeric amino acids. The suitability of D-enantiomeric peptides for in vivo applications, which are protease stable and less immunogenic than L-peptides, has already been demonstrated. The identified D-enantiomeric peptide MMD3 and its retro-inverso form, designated MMD3rev, inhibited in vitro fibrillization of the PHF6* peptide, the repeat domain of Tau as well as full-length Tau. Dynamic light scattering, pelleting assays and atomic force microscopy demonstrated that MMD3 prevents the formation of tau β-sheet-rich fibrils by diverting Tau into large amorphous aggregates. NMR data suggest that the D-enantiomeric peptides bound to Tau monomers with rather low affinity, but ELISA (enzyme-linked immunosorbent assay) data demonstrated binding to PHF6* and full length Tau fibrils. In addition, molecular insight into the binding mode of MMD3 to PHF6* fibrils were gained by in silico modelling. The identified PHF6*-targeting peptides were able to penetrate cells. The study establishes PHF6* fibril binding peptides consisting of D-enantiomeric amino acids as potential molecules for therapeutic and diagnostic applications in AD research.
000162730 536__ $$0G:(DE-HGF)POF4-352$$a352 - Disease Mechanisms (POF4-352)$$cPOF4-352$$fPOF IV$$x0
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000162730 650_7 $$2Other$$aAlzheimer's disease
000162730 650_7 $$2Other$$aD-peptides
000162730 650_7 $$2Other$$aphage display
000162730 650_7 $$2Other$$atau aggregation inhibitors
000162730 650_7 $$2Other$$atherapy
000162730 650_2 $$2MeSH$$aHumans
000162730 650_2 $$2MeSH$$aPeptide Library
000162730 650_2 $$2MeSH$$aPeptides: chemistry
000162730 650_2 $$2MeSH$$aPeptides: pharmacology
000162730 650_2 $$2MeSH$$aProtein Aggregates: drug effects
000162730 650_2 $$2MeSH$$atau Proteins: antagonists & inhibitors
000162730 650_2 $$2MeSH$$atau Proteins: metabolism
000162730 7001_ $$0P:(DE-2719)2812350$$aKaniyappan, Senthilvelrajan$$b1$$udzne
000162730 7001_ $$aAillaud, Isabelle$$b2
000162730 7001_ $$0P:(DE-2719)2811626$$aChandupatla, Ram Reddy$$b3$$udzne
000162730 7001_ $$0P:(DE-2719)9001275$$aRamirez, Lisa-Marie$$b4$$udzne
000162730 7001_ $$0P:(DE-2719)2810591$$aZweckstetter, Markus$$b5$$udzne
000162730 7001_ $$aHorn, Anselm H C$$b6
000162730 7001_ $$0P:(DE-2719)2541671$$aMandelkow, Eckhard$$b7$$udzne
000162730 7001_ $$aSticht, Heinrich$$b8
000162730 7001_ $$aFunke, Susanne Aileen$$b9
000162730 773__ $$0PERI:(DE-600)2020469-3$$a10.1002/cbic.202100287$$gVol. 22, no. 21, p. 3049 - 3059$$n21$$p3049 - 3059$$tChemBioChem$$v22$$x1439-7633$$y2021
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