Dawn Wong - Bivalent ligands derived from Huperzine A as acetylcholinesterase inhibitors

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      Publication Details (including relevant citation   information):

      Haviv, H.; Wong, D. M.; Silman, I.; Sussman, J.   L. Bivalent ligands derived from Huperzine A as   acetylcholinesterase inhibitors. Current Topics in Medicinal   Chemistry 2007, 7, 375-387. PMID: 17305579.   http://dx.doi.org/10.2174/156802607779941215



      The naturally occurring alkaloid Huperzine A (HupA) is an   acetylcholinesterase (AChE) inhibitor that has been used for   centuries as a Chinese folk medicine in the context of its source   plant Huperzia Serrata. The potency and relative safety   of HupA rendered it a promising drug for the ameliorative   treatment of Alzheimer's disease (AD) vis-à-vis the "cholinergic   hypothesis" that attributes the cognitive decrements associated   with AD to acetylcholine deficiency in the brain. However, recent   evidence supports a neuroprotective role for HupA, suggesting   that it could act as more than a mere palliative. Biochemical and   crystallographic studies of AChE revealed two potential binding   sites in the active-site gorge of AChE, one of which, the   “peripheral anionic site” at the mouth of the gorge, was   implicated in promoting aggregation of the beta amyloid (Abeta)   peptide responsible for the neurodegenerative process in AD. This   feature of AChE facilitated the development of dual-site binding   HupA-based bivalent ligands, in hopes of concomitantly increasing   AChE inhibition potency by utilizing the "chelate effect", and   protecting neurons from Abeta toxicity. Crystal structures of   AChE allowed detailed modeling and docking studies that were   instrumental in enhancing the understanding of underlying   principles of bivalent inhibitor-enzyme dynamics. This monograph   reviews two categories of HupA-based bivalent ligands, in which   HupA and HupA fragments serve as building blocks, with a focus on   the recently solved crystallographic structures of Torpedo   californica AChE in complex with such bifunctional agents.   The advantages and drawbacks of such structured-based drug   design, as well as species differences are highlighted and   discussed.

      Address (URL): http://dx.doi.org/10.2174/156802607779941215