Neurodegenerative diseases devastate millions of patients worldwide. These diseases typically target older individuals. In roughly 50 years over a quarter of the world will be over 65 years of age. The fastest growing demographic group in the developed world is people 85 and older. Said individuals have a very high probability (>50% and increasing with age) of acquiring one of these diseases. These diseases are currently untreatable, aside from alleviating the symptoms, and they can't be definitively diagnosed before death. These diseases are due to protein conformational changes involving formation of a toxic, soluble aggregate. Experimental studies have been unable to elucidate this structure. Computer simulations have, however, provided atomic resolution models for this state, and it was found that different proteins form the same rare structure during amyloidosis. This structure is being targeted here for the design of potential therapeutic and diagnostic agents. Specifically this proposal focuses on design of stable ?-sheet structures, their biophysical characterization, and binding to amyloidogenic proteins both during aggregation in solution (to test their ability to inhibit the process) and when the designed compounds are immobilized (to test their diagnostic ability). The designed compounds will be tested against various peptide/protein systems, including transthyretin, A?(1-42), amylin, and the prion protein.
The specific aims of this project are: (1) Design small, stable ?-sheet peptides/hairpins;(2) Test the ability of designed peptides to inhibit amyloid formation in solution;(3) Immobilize designs on agarose beads and test the ability of designed peptides to bind toxic oligomers;and (4) Characterize the structural properties of the designs and determine the spectroscopic signatures for ?-sheet.

Public Health Relevance

The population is aging and the incidence of amyloid diseases is growing to epidemic proportions. Currently most of these diseases cannot be definitively diagnosed without an autopsy and therapeutics are lacking. New approaches are needed to attack these debilitating diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM095808-02
Application #
8715831
Study Section
Macromolecular Structure and Function B Study Section (MSFB)
Program Officer
Wehrle, Janna P
Project Start
2013-08-06
Project End
2017-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
2
Fiscal Year
2014
Total Cost
$293,550
Indirect Cost
$103,550
Name
University of Washington
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Paranjapye, Natasha; Daggett, Valerie (2018) De Novo Designed ?-Sheet Peptides Inhibit Functional Amyloid Formation of Streptococcus mutans Biofilms. J Mol Biol 430:3764-3773
Maris, Nathan L; Shea, Dylan; Bleem, Alissa et al. (2018) Chemical and Physical Variability in Structural Isomers of an l/d ?-Sheet Peptide Designed To Inhibit Amyloidogenesis. Biochemistry 57:507-510
Bleem, Alissa; Francisco, Robyn; Bryers, James D et al. (2017) Designed ?-sheet peptides suppress amyloid formation in Staphylococcus aureus biofilms. NPJ Biofilms Microbiomes 3:16
Bleem, Alissa; Daggett, Valerie (2017) Structural and functional diversity among amyloid proteins: Agents of disease, building blocks of biology, and implications for molecular engineering. Biotechnol Bioeng 114:7-20
Cheng, Chin Jung; Koldsø, Heidi; Van der Kamp, Marc W et al. (2017) Simulations of membrane-bound diglycosylated human prion protein reveal potential protective mechanisms against misfolding. J Neurochem 142:171-182
Childers, Matthew Carter; Daggett, Valerie (2017) Insights from molecular dynamics simulations for computational protein design. Mol Syst Des Eng 2:9-33
Kellock, Jackson; Hopping, Gene; Caughey, Byron et al. (2016) Peptides Composed of Alternating L- and D-Amino Acids Inhibit Amyloidogenesis in Three Distinct Amyloid Systems Independent of Sequence. J Mol Biol 428:2317-2328
Cheng, Chin Jung; Daggett, Valerie (2014) Molecular dynamics simulations capture the misfolding of the bovine prion protein at acidic pH. Biomolecules 4:181-201
Hopping, Gene; Kellock, Jackson; Barnwal, Ravi Pratap et al. (2014) Designed ?-sheet peptides inhibit amyloid formation by targeting toxic oligomers. Elife 3:e01681
Towse, Clare-Louise; Hopping, Gene; Vulovic, Ivan et al. (2014) Nature versus design: the conformational propensities of D-amino acids and the importance of side chain chirality. Protein Eng Des Sel 27:447-55

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