Common structural features determine the effectiveness of carvedilol, daunomycin and rolitetracycline as inhibitors of Alzheimer β-amyloid fibril formation

Howlett, David; George, Ashley R.; Owen, Davina E.; Ward, Robin V.; Markwell, Roger E.

doi:10.1042/0264-6021:3430419

Cited by 90 publications

(96 citation statements)

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“…Initial structural analysis revealed that carvedilol, along with rolitetracycline and daunomycin, has a structural motif essential for binding to Aβ [115]. Subsequently, carvedilol was found to interfere with the oligomerization of Aβ [116].…”

Section: Antihypertensive Drugsmentioning

confidence: 99%

Drug Repositioning Approaches for the Discovery of New Therapeutics for Alzheimer's Disease

Kim

2015

Neurotherapeutics

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Summary Alzheimer's disease (AD) is the most common cause of dementia and represents one of the highest unmet needs in medicine today. Drug development efforts for AD have been encumbered by largely unsuccessful clinical trials in the last decade. Drug repositioning, a process of discovering a new therapeutic use for existing drugs or drug candidates, is an attractive and timely drug development strategy especially for AD. Compared with traditional de novo drug development, time and cost are reduced as the safety and pharmacokinetic properties of most repositioning candidates have already been determined. A majority of drug repositioning efforts for AD have been based on positive clinical or epidemiological observations or in vivo efficacy found in mouse models of AD. More systematic, multidisciplinary approaches will further facilitate drug repositioning for AD. Some experimental approaches include unbiased phenotypic screening using the library of available drug collections in physiologically relevant model systems (e.g. stem cell-derived neurons or glial cells), computational prediction and selection approaches that leverage the accumulating data resulting from RNA expression profiles, and genome-wide association studies. This review will summarize several notable strategies and representative examples of drug repositioning for AD.

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Section: Antihypertensive Drugsmentioning

confidence: 99%

Drug Repositioning Approaches for the Discovery of New Therapeutics for Alzheimer's Disease

Kim

2015

Neurotherapeutics

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“…Therefore, it was suggested (18) that RTC may be given intravenously or intramuscularly in serious bacterial infections when oral administration is not practicable. Although it is an antibiotic, it has been described (19) that RTC can effectively inhibit Ab fibril formation, which is associated with Alzheimer's disease. RTC has also been reported (20) to significantly inhibit the dengue virus propagation.…”

mentioning

confidence: 99%

Unraveling the Energetics and Mode of the Recognition of Antibiotics Tetracycline and Rolitetracycline by Bovine Serum Albumin

Choudhary

Kishore²

2012

Chem Biol Drug Des

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An understanding of the detailed energetics and mechanism of the binding of drugs with target proteins is essential for devising guidelines to synthesize new drugs. Binding of the antibiotic drugs tetracycline and rolitetracycline with serum albumin has been studied by a combination of isothermal titration calorimetry, differential scanning calorimetry, steady-state and time-resolved fluorescence, and circular dichroism spectroscopies. Both tetracycline and rolitetracycline bind to bovine serum albumin in a sequential manner with first binding being the major binding event with an association constant of the order of 10 4 for tetracycline and 10 3 for rolitetracycline, respectively. Ionic strength dependence and binding in the presence of tetrabutylammonium bromide and sucrose indicate involvement of a mix of hydrophobic, ionic, and hydrogen bonding interactions. The isothermal titration calorimetry results for the binding of these drugs to bovine serum albumin in the presence of warfarin and in the presence of each other indicate that both these drugs share binding site 2 on bovine serum albumin. The differential scanning calorimetry results provide quantitative information on the effect of drugs on the stability of bovine serum albumin. A comparison of isothermal titration calorimetry and fluorescence results demonstrates that the former technique has been able to explain the sequential binding events that can be missed by the fluorescence measurements.

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“…3B). This IC 50 value, which is reflective of a combination of binding affinity and stoichiometry, might suggest that compound 2 acts by binding A␤ 1-40 monomers to prevent nucleation, as has been suggested for the inhibition of A␤ 1-40 monomer aggregation by daunomycin (Howlett et al, 1999a) and the inhibition of A␤ 1-42 monomer aggregation by rifamycin and hematin (Necula et al, 2007b). Alternatively, compound 2 may bind on-pathway aggregates to prevent their progression into mature fibrillar structures.…”

Section: Discussionmentioning

confidence: 99%

“…Alternatively, small-molecule inhibitors have been observed to promote fibril formation but inhibit ongoing fibril growth (Williams et al, 2005) and to selectively inhibit different mechanisms of soluble aggregate growth (Moss et al, 2004). In addition, although some small molecules prevent both oligomer and fibril formation (Howlett et al, 1999a;De Felice et al, 2004;Yang et al, 2005;Bastianetto et al, 2006;Necula et al, 2007b), other inhibitors halt the appearance of oligomers without altering mature fibril formation (Necula et al, 2007a) or, conversely, block the appearance of mature fibrils while permitting oligomer formation (Lashuel et al, 2002;Ferrã o-Gonzales et al, 2005;Necula et al, 2007b). These qualitative studies demonstrate that small-molecule inhibitors of A␤ self-assembly can selectively act on various assembly pathways.…”

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confidence: 99%

Comparative Study of Inhibition at Multiple Stages of Amyloid-β Self-Assembly Provides Mechanistic Insight

Davis¹,

Soto-Ortega²,

Kotarek³

et al. 2009

Mol Pharmacol

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The "amyloid cascade hypothesis," linking self-assembly of the amyloid-␤ protein (A␤) to the pathogenesis of Alzheimer's disease, has led to the emergence of inhibition of A␤ self-assembly as a prime therapeutic strategy for this currently unpreventable and devastating disease. The complexity of A␤ selfassembly, which involves multiple reaction intermediates related by nonlinear and interconnected nucleation and growth mechanisms, provides multiple points for inhibitor intervention. Although a number of small-molecule inhibitors of A␤ selfassembly have been identified, little insight has been garnered concerning the point at which these inhibitors intervene within the A␤ assembly process. In the current study, a julolidine derivative is identified as an inhibitor of A␤ self-assembly. To gain insight into the mechanistic action of this inhibitor, the inhibition of fibril formation from monomeric protein is assessed quantitatively and compared with the inhibition of two distinct mechanisms of growth for soluble A␤ aggregation intermediates. This compound is observed to significantly inhibit soluble aggregate growth by lateral association while having little effect on soluble aggregate elongation via monomer addition. In addition, inhibition of soluble A␤ aggregate association exhibits an IC 50 with a somewhat lower stoichiometric ratio than the IC 50 determined for inhibition of fibril formation from monomeric A␤. This quantitative comparison of inhibition within multiple A␤ self-assembly assays suggests that this compound binds the lateral surface of on-pathway intermediates exhibiting a range of sizes to prevent their association with other aggregates, which is required for further assembly into mature fibrils.Alzheimer's disease (AD) is currently the most common type of dementia, affecting an estimated 5.2 million Americans (Alzheimer's Association, 2008). As the life expectancy in the United States and other postindustrialized nations increases, AD presents a burgeoning epidemic. AD initially affects short-term memory and progresses to include pervasive cognitive and emotional dysfunction. These manifested symptoms are hypothesized to result from a cascade of events initiated by the self-assembly of monomeric amyloid-␤ protein (A␤), leading first to the formation of soluble aggregates and later progressing into larger insoluble fibrils, which ultimately deposit in the extracellular space of the brain parenchyma. This "amyloid cascade hypothesis" is supported by experimental evidence (Walsh and Selkoe, 2007), including genetic correlations, transgenic animal models, and cell culture studies, and has established the inhibition of A␤ self-assembly as a prime therapeutic strategy in the fight against AD.Several small molecules that inhibit the in vitro formation of amyloid fibrils from monomeric A␤ have been identified (Findeis, 2000;Hamaguchi et al., 2006;LeVine, 2007). Studies using quantitative measures of inhibition assembled from light scattering measurements, thioflavin T (ThT) fluorescence, or immun...

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Common structural features determine the effectiveness of carvedilol, daunomycin and rolitetracycline as inhibitors of Alzheimer β-amyloid fibril formation

Cited by 90 publications

References 0 publications

Drug Repositioning Approaches for the Discovery of New Therapeutics for Alzheimer's Disease

Drug Repositioning Approaches for the Discovery of New Therapeutics for Alzheimer's Disease

Unraveling the Energetics and Mode of the Recognition of Antibiotics Tetracycline and Rolitetracycline by Bovine Serum Albumin

Comparative Study of Inhibition at Multiple Stages of Amyloid-β Self-Assembly Provides Mechanistic Insight

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