New methods to explore marine resources for Alzheimer's therapeutics.
Despite the long history of drug discovery from natural sources, the marine environment, which covers 70% of the Earth's surface, is still relatively unexplored. Intense competition for limited resources drives the evolution of specific and potent chemical defenses distinct from their terrestrial counterparts. Based on this rationale, we recently began screening extracts derived from marine invertebrate and cyanobacterial samples for BACE-1 inhibitors in a chemiluminescent enzyme-fragment complementation (EFC) assay. The results of this broad screening are presented here, along with our progress towards the development of a secondary LC-MS homogeneous affinity assay. Incubation of the extracts active in the EFC assay with BACE1, subsequent isolation of the enzyme-inhibitor complex and then analysis of the small molecule inhibitor by LC-MS rapidly links a chemical structure to biological activity. This approach enables the rapid target-orientated discovery of BACE-1 inhibitors from marine sources.
Williams
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P
Department of Chemistry & Cancer Research Center of Hawai'i, University of Hawai'i at Manoa, 96822, USA. philipwi@hawaii.edu
Sorribas
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A
Liang
Z
Z
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology* / Q000503:physiopathology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000458:Cyanobacteria / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D057075:Enzyme Assays / Q000379:methods; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000302:isolation & purification* / Q000494:pharmacology; D006801:Humans; D007448:Invertebrates / Q000737:chemistry / Q000378:metabolism; D008386:Marine Biology / Q000379:methods* / Q000639:trends; D015394:Molecular Structure
D004791:Enzyme Inhibitors; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human