Beta-secretase Inhibitors and Amyloid Reduction Therapy for Alzheimer's Disease

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Amyloid reduction is an attractive therapeutic approach for Alzheimer disease (AD) and the inhibition of β-secretase (memapsin 2, BACE1), the aspartic protease that initiates the processing of APP leading to the production of Aβ, has emerged as a major area for developing inhibitor drugs. During the past ten years, various strategies have been applied in the evolution of β-secretase inhibitors into a drug candidate. A successful drug candidate for β-secretase is likely to be a mimic to the catalytic transition-state. It needs to be potent with Ki near low nM range, size small enough to penetrate the blood-brain-barrier, selective vs. other human aspartic proteases and processes good drug properties. The first potent β-secretase inhibitor, OM99-2 (892 Da; Ki = 1.6 nM), contained eight residues with the scissile bond substituted by a hydroxyethylene transition-state isostere. To facilitate the use of structure-based evolution of inhibitor structure, we determined the crystal structure of the catalytic domain of β-secretase bound to OM99-2. For the reduction of inhibitor size, the loss of potency from the removal of outside residues P4, P3' and P4' was compensated by the increase in protein-ligand interaction of central residues from P3 to P2'. Structural modules discovered for selectivity and potency were incorporated into new inhibitors. The path of inhibitor structural evolution was guided by data from enzyme kinetics and Aβ inhibition in cells and mice. This process has produced some inhibitors in 600s Da range with good drug-like properties. Inhibitor GRL-8234, Ki of 1.2 nM and cellular IC50 of about 1 nM, has good selectivity vs. cathepsin D and memapsin 1 and brain penetration of about 4%. Administration of GRL-8234 at 50 mg/Kg reduced Aβ by about 60% in the plasma and about interstitial Aβ by over 50% in the brain of Tg2576 mice. To test the rescue of age-related cognitive decline in a transgenic AD mouse model, we continuous delivered GRL-8234 in Tg2576 for up to about 8 months. Such treatment produced significant difference in cognitive performance over the control mice in Morris Water Maze in escape latency, time in quadrant and annulus crossing index. The cognitive performance of the inhibitor treated mice, which had also reduced brain amyloid plaques, was near that of the wild type mice. These developments suggest that the significant progress has been made in the development of memapsin 2 inhibitors toward a drug candidate and the future of this line of drug development for an AD drug appears encouraging. (Jordan Tang, Oklahoma Medical Research Foundation) ...http://www.nyas.org/events/eventDetail.asp?eventID=13408&date=3/24/2009

Finding the over-50s functional foods market

The over-50s have peculiar nutrition needs that, increasingly, are being catered to by functional foods makers as Shane Starling found out at a recent conference on the subject in Amsterdam. He spoke with chair, Dr Sian Astley, from the UK-based Institute of Food Research, after the event. ...http://www.nutraingredients.com

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