|
rdf:type |
|
|
lifeskim:mentions |
|
|
pubmed:issue |
21
|
|
pubmed:dateCreated |
2009-7-20
|
|
pubmed:databankReference |
|
|
pubmed:abstractText |
BACE-1 (beta-site amyloid precursor protein cleaving enzyme), a prominent target in Alzheimer's disease drug discovery efforts, was surveyed using Tethering technology to discover small molecule fragment ligands that bind to the enzyme active site. Screens of a library of >15000 thiol-containing fragments versus a panel of BACE-1 active site cysteine mutants under redox-controlled conditions revealed several novel amine-containing fragments that could be selectively captured by subsets of the tethering sites. For one such hit class, defined by a central aminobenzylpiperidine (ABP) moiety, X-ray crystal structures of BACE mutant-disulfide conjugates revealed that the fragment bound by engaging both catalytic aspartates with hydrogen bonds. The affinities of ABP fragments were improved by structure-guided chemistry, first for conjugation as thiol-containing fragments and then for stand-alone, noncovalent inhibition of wild-type (WT) BACE-1 activity. Crystallography confirmed that the inhibitors bound in exactly the same mode as the disulfide-conjugated fragments that were originally selected from the screen. The ABP ligands represent a new type of nonpeptidic BACE-1 inhibitor motif that has not been described in the aspartyl protease literature and may serve as a starting point for the development of BACE-1-directed Alzheimer's disease therapeutics.
|
|
pubmed:language |
eng
|
|
pubmed:journal |
|
|
pubmed:citationSubset |
IM
|
|
pubmed:chemical |
|
|
pubmed:status |
MEDLINE
|
|
pubmed:month |
Jun
|
|
pubmed:issn |
1520-4995
|
|
pubmed:author |
pubmed-author:AllisonTimothy JTJ,
pubmed-author:BallingerMarcus DMD,
pubmed-author:CaryDouglas RDR,
pubmed-author:ColussiDennisD,
pubmed-author:FahrBruce TBT,
pubmed-author:FuciniRaymond VRV,
pubmed-author:HuntSS,
pubmed-author:JacobsJeffrey WJW,
pubmed-author:LamMelissa BMB,
pubmed-author:LindKenneth EKE,
pubmed-author:LuYafanY,
pubmed-author:McDowellRobert SRS,
pubmed-author:MunshiSanjeev KSK,
pubmed-author:PennyDavid MDM,
pubmed-author:PhamPhuonglyP,
pubmed-author:PietrakBethB,
pubmed-author:RandalMikeM,
pubmed-author:RomanowskiMichael JMJ,
pubmed-author:ThomasAnila EAE,
pubmed-author:WalchOO,
pubmed-author:WilkinsonJennifer MJM,
pubmed-author:YangWenjinW
|
|
pubmed:issnType |
Electronic
|
|
pubmed:day |
2
|
|
pubmed:volume |
48
|
|
pubmed:owner |
NLM
|
|
pubmed:authorsComplete |
Y
|
|
pubmed:pagination |
4488-96
|
|
pubmed:meshHeading |
pubmed-meshheading:19284778-Amyloid Precursor Protein Secretases,
pubmed-meshheading:19284778-Biocatalysis,
pubmed-meshheading:19284778-Catalytic Domain,
pubmed-meshheading:19284778-Cysteine,
pubmed-meshheading:19284778-Drug Discovery,
pubmed-meshheading:19284778-Drug Evaluation, Preclinical,
pubmed-meshheading:19284778-Enzyme Inhibitors,
pubmed-meshheading:19284778-Humans,
pubmed-meshheading:19284778-Ligands,
pubmed-meshheading:19284778-Models, Molecular,
pubmed-meshheading:19284778-Molecular Conformation,
pubmed-meshheading:19284778-Mutation,
pubmed-meshheading:19284778-Peptides,
pubmed-meshheading:19284778-Piperidines,
pubmed-meshheading:19284778-Structure-Activity Relationship
|
|
pubmed:year |
2009
|
|
pubmed:articleTitle |
Fragment-based discovery of nonpeptidic BACE-1 inhibitors using tethering.
|
|
pubmed:affiliation |
Department of Chemistry, Sunesis Pharmaceuticals, Inc., 395 Oyster Point Boulevard,South San Francisco, California 94080, USA. wyang@eigerbio.com
|
|
pubmed:publicationType |
Journal Article
|
