Small molecule ligands rationally designed to complement β-sheet hydrogen-bond patterns present in fibrils, but that halt continuation of the β-sheet, e.g., aminopyrazole derivatives, have been known for some time (1,2). These β-sheet-complementing substances, however, lack specificity for fibrils built of a certain protein or peptide.
Sievers and colleagues report a very elegant study on the rational, 3-dimensional structure-based design of small peptide ligands that specifically bind to their target molecules in fibrillar conformation. Their decisive advantage over the aforementioned β-sheet-complementing substances is specificity. Sievers et al. clearly show that they arrive at peptides that bind specifically and show interesting activities in vitro.
The researchers combine the advantages of β-sheet-complementing compounds with those of substances that can specifically bind a certain amyloidogenic peptide or protein—more or less irrespective of its conformation.
Recently, we described a distantly similar approach when we covalently linked a classical β-sheet-complementing substance with a peptide that specifically binds Aβ. The resulting hybrid substance also was very efficient in in-vitro assays (3). D3, the peptide moiety of this hybrid substance is a D-enantiomeric peptide and has already been shown to be very efficient in animal models in vivo, where it reduced the amyloid plaque load and improved cognitive behavior of transgenic mice, even after oral treatment (4).
This shows that peptides, especially D-enantiomeric peptides, may well be suitable for drug development.
We look forward to results from in vivo studies of these new peptides. We hope the researchers will be successful. In our view, fighting Alzheimer’s disease and AIDS is worth every effort.
References:
Permanne B, Adessi C, Fraga S, Frossard MJ, Saborio GP, Soto C.
Are beta-sheet breaker peptides dissolving the therapeutic problem of Alzheimer's disease?.
J Neural Transm Suppl. 2002;(62):293-301.
PubMed.
Nagel-Steger L, Demeler B, Meyer-Zaika W, Hochdörffer K, Schrader T, Willbold D.
Modulation of aggregate size- and shape-distributions of the amyloid-beta peptide by a designed beta-sheet breaker.
Eur Biophys J. 2010 Feb;39(3):415-22.
PubMed.
Müller-Schiffmann A, März-Berberich J, Andreyeva A, Rönicke R, Bartnik D, Brener O, Kutzsche J, Horn AH, Hellmert M, Polkowska J, Gottmann K, Reymann KG, Funke SA, Nagel-Steger L, Moriscot C, Schoehn G, Sticht H, Willbold D, Schrader T, Korth C.
Combining independent drug classes into superior, synergistically acting hybrid molecules.
Angew Chem Int Ed Engl. 2010 Nov 8;49(46):8743-6.
PubMed.
Aileen Funke S, van Groen T, Kadish I, Bartnik D, Nagel-Steger L, Brener O, Sehl T, Batra-Safferling R, Moriscot C, Schoehn G, Horn AH, Müller-Schiffmann A, Korth C, Sticht H, Willbold D.
Oral treatment with the d-enantiomeric peptide D3 improves the pathology and behavior of Alzheimer's Disease transgenic mice.
ACS Chem Neurosci. 2010 Sep 15;1(9):639-48. Epub 2010 Aug 2
PubMed.
Comments
Institut für Strukturbiologie und Biophysik
Small molecule ligands rationally designed to complement β-sheet hydrogen-bond patterns present in fibrils, but that halt continuation of the β-sheet, e.g., aminopyrazole derivatives, have been known for some time (1,2). These β-sheet-complementing substances, however, lack specificity for fibrils built of a certain protein or peptide.
Sievers and colleagues report a very elegant study on the rational, 3-dimensional structure-based design of small peptide ligands that specifically bind to their target molecules in fibrillar conformation. Their decisive advantage over the aforementioned β-sheet-complementing substances is specificity. Sievers et al. clearly show that they arrive at peptides that bind specifically and show interesting activities in vitro.
The researchers combine the advantages of β-sheet-complementing compounds with those of substances that can specifically bind a certain amyloidogenic peptide or protein—more or less irrespective of its conformation.
Recently, we described a distantly similar approach when we covalently linked a classical β-sheet-complementing substance with a peptide that specifically binds Aβ. The resulting hybrid substance also was very efficient in in-vitro assays (3). D3, the peptide moiety of this hybrid substance is a D-enantiomeric peptide and has already been shown to be very efficient in animal models in vivo, where it reduced the amyloid plaque load and improved cognitive behavior of transgenic mice, even after oral treatment (4).
This shows that peptides, especially D-enantiomeric peptides, may well be suitable for drug development.
We look forward to results from in vivo studies of these new peptides. We hope the researchers will be successful. In our view, fighting Alzheimer’s disease and AIDS is worth every effort.
References:
Permanne B, Adessi C, Fraga S, Frossard MJ, Saborio GP, Soto C. Are beta-sheet breaker peptides dissolving the therapeutic problem of Alzheimer's disease?. J Neural Transm Suppl. 2002;(62):293-301. PubMed.
Nagel-Steger L, Demeler B, Meyer-Zaika W, Hochdörffer K, Schrader T, Willbold D. Modulation of aggregate size- and shape-distributions of the amyloid-beta peptide by a designed beta-sheet breaker. Eur Biophys J. 2010 Feb;39(3):415-22. PubMed.
Müller-Schiffmann A, März-Berberich J, Andreyeva A, Rönicke R, Bartnik D, Brener O, Kutzsche J, Horn AH, Hellmert M, Polkowska J, Gottmann K, Reymann KG, Funke SA, Nagel-Steger L, Moriscot C, Schoehn G, Sticht H, Willbold D, Schrader T, Korth C. Combining independent drug classes into superior, synergistically acting hybrid molecules. Angew Chem Int Ed Engl. 2010 Nov 8;49(46):8743-6. PubMed.
Aileen Funke S, van Groen T, Kadish I, Bartnik D, Nagel-Steger L, Brener O, Sehl T, Batra-Safferling R, Moriscot C, Schoehn G, Horn AH, Müller-Schiffmann A, Korth C, Sticht H, Willbold D. Oral treatment with the d-enantiomeric peptide D3 improves the pathology and behavior of Alzheimer's Disease transgenic mice. ACS Chem Neurosci. 2010 Sep 15;1(9):639-48. Epub 2010 Aug 2 PubMed.
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