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Lifting the veil on amyloid drug design.

Tiller KE, Tessier PM - Elife (2013)

Bottom Line: High resolution structures and computational methods have been used to identify compounds that prevent amyloid fibrils associated with Alzheimer's disease from dissociating into toxic species.

View Article: PubMed Central - PubMed

Affiliation: is in the Center for Biotechnology & Interdisciplinary Studies, Department of Chemical and Biological Engineering , Rensselaer Polytechnic Institute , New York , United States tillek@rpi.edu.

ABSTRACT
High resolution structures and computational methods have been used to identify compounds that prevent amyloid fibrils associated with Alzheimer's disease from dissociating into toxic species.

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Related in: MedlinePlus

The Alzheimer’s peptide—initially soluble and benign when in monomeric form—assembles into oligomers, which are highly toxic to cells, and amyloid fibrils, which have low toxicity. Molecules that bind to and stabilize fibrils (example shown in blue) can inhibit amyloid toxicity by preventing the dissociation of fibrils into toxic oligomers, or into monomers that can reassemble into toxic oligomers. The yellow and red arrows in the fibrils represent individual β-strands. The inset shows an expanded view as seen from the front (left) and side (right). Inset images were adapted by Lin Jiang from Figure 1—figure supplement 2 of Jiang et al., 2013.
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fig1: The Alzheimer’s peptide—initially soluble and benign when in monomeric form—assembles into oligomers, which are highly toxic to cells, and amyloid fibrils, which have low toxicity. Molecules that bind to and stabilize fibrils (example shown in blue) can inhibit amyloid toxicity by preventing the dissociation of fibrils into toxic oligomers, or into monomers that can reassemble into toxic oligomers. The yellow and red arrows in the fibrils represent individual β-strands. The inset shows an expanded view as seen from the front (left) and side (right). Inset images were adapted by Lin Jiang from Figure 1—figure supplement 2 of Jiang et al., 2013.

Mentions: Some of the most debilitating human disorders—including Alzheimer’s, Parkinson’s and Huntington’s diseases—are marked by the inappropriate assembly of peptides and proteins into particles of various sizes, structures and toxicities. These range from highly toxic small oligomers, each consisting of a few monomers, to large insoluble aggregates known as amyloid fibrils, which are less toxic (Figure 1). Much effort has therefore focused on identifying compounds that inhibit oligomer and fibril assembly or promote their disassembly (Hard and Lendel, 2012). However, progress has been hampered by a lack of detailed knowledge of the structure of amyloid oligomers and fibrils, particularly when they are bound to inhibitor molecules. Now, in eLife, Lin Jiang, David Eisenberg and co-workers at the University of California, Los Angeles, have designed several new compounds that reduce amyloid toxicity (Jiang et al., 2013). The starting point for their study was the high resolution structure of an Alzheimer’s peptide in an amyloid-like conformation bound to an inhibitor molecule (Landau et al., 2011).Figure 1.


Lifting the veil on amyloid drug design.

Tiller KE, Tessier PM - Elife (2013)

The Alzheimer’s peptide—initially soluble and benign when in monomeric form—assembles into oligomers, which are highly toxic to cells, and amyloid fibrils, which have low toxicity. Molecules that bind to and stabilize fibrils (example shown in blue) can inhibit amyloid toxicity by preventing the dissociation of fibrils into toxic oligomers, or into monomers that can reassemble into toxic oligomers. The yellow and red arrows in the fibrils represent individual β-strands. The inset shows an expanded view as seen from the front (left) and side (right). Inset images were adapted by Lin Jiang from Figure 1—figure supplement 2 of Jiang et al., 2013.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3713451&req=5

fig1: The Alzheimer’s peptide—initially soluble and benign when in monomeric form—assembles into oligomers, which are highly toxic to cells, and amyloid fibrils, which have low toxicity. Molecules that bind to and stabilize fibrils (example shown in blue) can inhibit amyloid toxicity by preventing the dissociation of fibrils into toxic oligomers, or into monomers that can reassemble into toxic oligomers. The yellow and red arrows in the fibrils represent individual β-strands. The inset shows an expanded view as seen from the front (left) and side (right). Inset images were adapted by Lin Jiang from Figure 1—figure supplement 2 of Jiang et al., 2013.
Mentions: Some of the most debilitating human disorders—including Alzheimer’s, Parkinson’s and Huntington’s diseases—are marked by the inappropriate assembly of peptides and proteins into particles of various sizes, structures and toxicities. These range from highly toxic small oligomers, each consisting of a few monomers, to large insoluble aggregates known as amyloid fibrils, which are less toxic (Figure 1). Much effort has therefore focused on identifying compounds that inhibit oligomer and fibril assembly or promote their disassembly (Hard and Lendel, 2012). However, progress has been hampered by a lack of detailed knowledge of the structure of amyloid oligomers and fibrils, particularly when they are bound to inhibitor molecules. Now, in eLife, Lin Jiang, David Eisenberg and co-workers at the University of California, Los Angeles, have designed several new compounds that reduce amyloid toxicity (Jiang et al., 2013). The starting point for their study was the high resolution structure of an Alzheimer’s peptide in an amyloid-like conformation bound to an inhibitor molecule (Landau et al., 2011).Figure 1.

Bottom Line: High resolution structures and computational methods have been used to identify compounds that prevent amyloid fibrils associated with Alzheimer's disease from dissociating into toxic species.

View Article: PubMed Central - PubMed

Affiliation: is in the Center for Biotechnology & Interdisciplinary Studies, Department of Chemical and Biological Engineering , Rensselaer Polytechnic Institute , New York , United States tillek@rpi.edu.

ABSTRACT
High resolution structures and computational methods have been used to identify compounds that prevent amyloid fibrils associated with Alzheimer's disease from dissociating into toxic species.

Show MeSH
Related in: MedlinePlus