. A molecular dynamics study of the interaction of D-peptide amyloid inhibitors with their target sequence reveals a potential inhibitory pharmacophore conformation. J Mol Biol. 2008 Oct 31;383(1):266-80. PubMed.


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  1. This is a thorough study that illustrates the importance of molecular dynamics simulations in search for inhibitors of amyloid aggregation. Esteras-Chopo et al. assume a structural model of the fibrillization nuclei of an amyloidogenic amino acid sequence STVIIE, a prototype of a protein associated with amyloid diseases. Using the structural model, interactions between the fibrillization nuclei and D-peptides previously shown to inhibit amyloid formation in vitro are examined.

    The results based on examination of three different inhibitor sequences suggest that D-Trp and D-Phe residues destabilize the fibrillization nucleus of STVIIE by breaking the register of hydrogen bonding, resulting in a transition from an ordered extended β-sheet (amyloid) structure into a disordered oligomeric (non-amyloid) complex that does not evolve into fibrils.

    Further, the authors show that some known small-molecule amyloid inhibitors (polycyclic aromatic molecules) such as curcumin, Congo red, and phenol red are characterized by a similar arrangement of aromatic rings to the one found in peptide inhibitors. Esteras-Chopo et al. use an experimental assay to show that phenol red, although to a lesser degree than the peptide counterparts, also acts as an inhibitor of STVIIE fibrillization. Based on the above findings, this study suggests the essential chemical features, so-called pharmacophores, needed to interfere with amyloidogenic pathways.

    While the study is beautifully conducted and executed, the basic assumptions need to be closely re-evaluated. The authors assume that breaking the structure of the fibrillization nucleus is key to drug design against amyloid diseases. Substantial evidence indicates that oligomers of amyloidogenic proteins are most likely the proximate toxins in several neurological disorders, including the two most prevalent forms of dementia, Alzheimer and Parkinson disease. Esteras-Chopo et al. assume that the oligomerization pathway will be inhibited along with the inhibition of fibrillization nucleus. However, most studies indicate that oligomers are characterized by substantially lower amounts of β-sheet structure and are thus likely structurally different from fibrils. Consequently, the pharmacophores that target oligomers may not coincide with those that target fibrils.

    Moreover, recent studies examining structure-toxicity relationship in Alzheimer's amyloid-β protein assembly [1-3] clearly demonstrate that inhibition of assembly is not necessarily correlated with toxicity inhibition. In fact, inhibiting fibril formation may result in accumulation of non-fibrillar oligomeric assemblies that could be potentially more toxic than the oligomers formed in the absence of any inhibitor.

    In conclusion, however difficult and elusive such research may be, protein-specific high-resolution oligomeric structures are needed to develop efficient oligomer-targeted therapeutic approaches.


    . Inositol stereoisomers stabilize an oligomeric aggregate of Alzheimer amyloid beta peptide and inhibit abeta -induced toxicity. J Biol Chem. 2000 Jun 16;275(24):18495-502. PubMed.

    . Cyclohexanehexol inhibitors of Abeta aggregation prevent and reverse Alzheimer phenotype in a mouse model. Nat Med. 2006 Jul;12(7):801-8. PubMed.

    . C-terminal peptides coassemble into Abeta42 oligomers and protect neurons against Abeta42-induced neurotoxicity. Proc Natl Acad Sci U S A. 2008 Sep 16;105(37):14175-80. PubMed.

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