Oral Presentation 2014 International Biophysics Congress

A new supramolecular strategy for the inhibition of amyloid fibrillation (#175)

Hong Hee Lee 1 , Tae Su Choi 1 , Hugh I. Kim 1
  1. POSTECH, Pohang, Gyengsangbukdo, South Korea

As rise of the life expectancy have become the worldwide phenomena, risk of the degenerative diseases have increased. Referring the World Health Organization report, patients with dementia is currently estimated at 35.6 million, and this number will double by 2030 and above triple by 2050. Most common form of a dementia is Alzheimer’s disease which is categorized as the amyloidosis.1 The amyloidosis is the group of diseases related to the proteins which form fibril-like aggregate. These aggregates are energetically highly favored, and due to its self-catalytic characteristic of aggregates, the aggregates are condensed with the time flow. Accordingly, the amyloidosis shows the features of age-related, degenerative diseases, such as Alzheimer’s,2 Parkinson’s disease3 and type II diabetes.4 In consequence, understanding the aggregation mechanism and inhibiting the aggregation formation is valuable to treat the amyloidosis.

Despite the therapeutic significance, developing a therapeutic method of amyloidosis is still difficult.5 Small molecular inhibitors are widely investigated, but they have low binding affinity (Ka = ~102-104 M-1) and their activating mechanisms are still vague. Therefore, a rational design is essential for the breakthrough in developing a new inhibition method for the amyloidosis. Here, we present a new supramolecular strategy for inhibiting amyloid fibrillation using cucurbit[7]uril (CB[7]) with insulin and b-amyloid, as a representative structured and unstructured amyloid proteins. CB[7] specifically binds to Phe residues, which is crucial for the hydrophobic interaction during the amyloid fibrillation.6 This study suggests that Phe-specific interactions of CB[7] can modulate the intermolecular interaction of amyloid proteins from the monomeric to multimeric states, providing potential applications for developing a therapeutic strategy of amyloidosis.7

  1. World Health Organization and Alzheimer’s Disease International, World Health Organization Report 2012
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  4. S. B. Prusiner, Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 13363-13383
  5. T. Hard, C. Lendel, J. Mol. Biol. 2012, 421, 441-465
  6. S. Y. Seong, P. Matzinger, Nat. Rev. Immunol. 2004, 4, 469-478
  7. H. H. Lee, T. S. Choi, et al. Angew. Chem. Int Ed. 2014 (in press)