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P3‐296: BACE1 is not the rate‐limiting enzyme in Aβ production in the brains of APPswe transgenic mice: Pharmacological characterization of BACE1 using novel brain penetrant inhibitors.
Author(s) -
Riddell D.R.,
Atchison K.,
Yu D.,
Turner J.,
Wang E.,
Gonzales C.,
Warwick H.,
Kim J.,
Malamas M.,
Wagner E.,
Aschmies S.,
Albinson K.,
Erdel J.,
Gunawan I.,
RevillaSanchez R.,
Takano K.,
Warren N.,
Fang K.,
Bard J.,
Hirst W.,
Pangalos M.,
Moss S.,
Haydon P.G.,
Robichaud A.,
Reinhart P.
Publication year - 2009
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2009.04.967
Subject(s) - in vivo , neurodegeneration , in vitro , chemistry , amyloid precursor protein , genetically modified mouse , enzyme , endogeny , pharmacology , cleavage (geology) , transgene , peptide , amyloid precursor protein secretase , penetrant (biochemical) , biochemistry , alzheimer's disease , medicine , biology , disease , gene , paleontology , microbiology and biotechnology , organic chemistry , fracture (geology)
Background: Protein-protein interactions are a principal regulatory mechanism in biology, but also a common source of pathogenesis. Many proteins are susceptible to misfolding and amyloidogenesis, leading to human disease via a gain of pathogenic function. The assembly of these misfolded proteins into a variety of aggregates is linked to numerous debilitating diseases such as neurodegenerative diseases, polyneuropathies and cardiomyopathies. Recent studies from three diverse disciplines, neuropathology, genetics, and biophysics, have indicated a novel target for therapeutic intervention: ordered protein aggregation. However, previous small molecule based approaches to inhibit protein-protein interactions, particularly aggregating proteins, have had limited success, and subsequently inhibition of protein-protein interactions remains the "Holy Grail" of drug design. Methods: A few years ago we developed a new strategy that combines emerging chemical and biological technologies to address this problem. This strategy enables small molecules to recruit the steric bulk provided by the chaperone FKBP to the aggregating peptide and to thus effectively block the formation of pathogenic protein aggregates. Results: We have now expanded on this approach and have designed bifunctional small molecules that are able to recruit other cellular proteins that have been shown to modulate A-beta aggregation and to genetically interact with the A-beta aggregation pathway. To identify novel compounds that bind to different aggregation species of A-beta, we have used both rational design as well as an unbiased high throughput screening (HTS) approach, which we complement with computational scaffold hopping to identify structural analogs of hits. Conclusions: In addition to their potential as a starting point for the development of novel therapeutic agents for AD, these bifunctional small molecules can also be used as chemical probes to address unanswered questions regarding the molecular mechanisms underlying the pathogenesis of AD.