Identification of small-molecule inhibitors of the Abeta-ABAD interaction.

Department of Medicine, Columbia University, New York, NY 10032, USA.
Bioorganic & Medicinal Chemistry Letters (Impact Factor: 2.33). 10/2006; 16(17):4657-60. DOI: 10.1016/j.bmcl.2006.05.099
Source: PubMed

ABSTRACT The interaction of amyloid beta peptide (Abeta) and Abeta-binding alcohol dehydrogenase (ABAD) was recently implicated in the pathogenesis of Alzheimer's disease (AD). Using an ELISA-based screening assay, we identified frentizole, an FDA-approved immunosuppressive drug, as a novel inhibitor of the Abeta-ABAD interaction. Analysis of the frentizole structure-activity relationship led to identification of a novel benzothiazole urea with a 30-fold improvement in potency.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Amyloid beta (Aβ) binding alcohol dehydrogenase (ABAD) is a cellular cofactor for promoting (Aβ)-mediated mitochondrial and neuronal dysfunction, and cognitive decline in transgenic Alzheimer's disease (AD) mouse models. Targeting mitochondrial ABAD may represent a novel therapeutic strategy against AD. Here, we report the biological activity of small molecule ABAD inhibitors. Using in vitro surface plasmon resonance (SPR) studies, we synthesized compounds with strong binding affinities for ABAD. Further, these ABAD inhibitors (ABAD-4a and 4b) reduced ABAD enzyme activity and administration of phosphonate derivatives of ABAD inhibitors antagonized calcium-mediated mitochondrial swelling. Importantly, these compounds also abolished Aβ-induced mitochondrial dysfunction as shown by increased cytochrome c oxidase and adenosine-5'-triphosphate levels, suggesting protective mitochondrial function effects of these synthesized compounds. Thus, these compounds are potential candidates for further pharmacologic development to target ABAD to improve mitochondrial function.
    Current Alzheimer research 01/2014; · 4.97 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Flash vacuum pyrolyses and photolyses of 2-methylthio-N-(arenylidene)anilines 2a–h are new and convenient methods for the syntheses of 2-arylbenzothiazoles 1a–h.
    Tetrahedron Letters 06/2008; 49(26):4145-4146. · 2.39 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Our previous studies have revealed that amyloid β (Aβ)-binding alcohol dehydrogenase (ABAD) decoy peptide antagonizes Aβ42-induced neurotoxicity. However, whether it improves oxidative stress injury remains unclear. In this study, a recombinant adenovirus constitutively secreting and expressing Aβ-ABAD decoy peptide (rAAV/ABAD-DP-6His) was successfully constructed. Our results showed that rAAV/ABAD-DP-6His increased superoxide dismutase activity in hydrogen peroxide-induced oxidative stress-mediated injury of PC12 cells. Moreover, rAAV/ABAD-DP-6His decreased malondialdehyde content, intracellular Ca(2+) concentration, and the level of reactive oxygen species. rAAV/ABAD-DP-6His maintained the stability of the mitochondrial membrane potential. In addition, the ATP level remained constant, and apoptosis was reduced. Overall, the results indicate that rAAV/ABAD-DP-6His generates the fusion peptide, Aβ-ABAD decoy peptide, which effectively protects PC12 cells from oxidative stress injury induced by hydrogen peroxide, thus exerting neuroprotective effects.
    Neural Regeneration Research 03/2014; 9(5):481-8. · 0.23 Impact Factor