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  • 1
    Publication Date: 2012-12-14
    Description: The clinical efficacy and safety of a drug is determined by its activity profile across many proteins in the proteome. However, designing drugs with a specific multi-target profile is both complex and difficult. Therefore methods to design drugs rationally a priori against profiles of several proteins would have immense value in drug discovery. Here we describe a new approach for the automated design of ligands against profiles of multiple drug targets. The method is demonstrated by the evolution of an approved acetylcholinesterase inhibitor drug into brain-penetrable ligands with either specific polypharmacology or exquisite selectivity profiles for G-protein-coupled receptors. Overall, 800 ligand-target predictions of prospectively designed ligands were tested experimentally, of which 75% were confirmed to be correct. We also demonstrate target engagement in vivo. The approach can be a useful source of drug leads when multi-target profiles are required to achieve either selectivity over other drug targets or a desired polypharmacology.〈br /〉〈br /〉〈a href="" target="_blank"〉〈img src="" border="0"〉〈/a〉   〈a href="" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Besnard, Jeremy -- Ruda, Gian Filippo -- Setola, Vincent -- Abecassis, Keren -- Rodriguiz, Ramona M -- Huang, Xi-Ping -- Norval, Suzanne -- Sassano, Maria F -- Shin, Antony I -- Webster, Lauren A -- Simeons, Frederick R C -- Stojanovski, Laste -- Prat, Annik -- Seidah, Nabil G -- Constam, Daniel B -- Bickerton, G Richard -- Read, Kevin D -- Wetsel, William C -- Gilbert, Ian H -- Roth, Bryan L -- Hopkins, Andrew L -- 083481/Wellcome Trust/United Kingdom -- BB/FOF/PF/15/09/Biotechnology and Biological Sciences Research Council/United Kingdom -- BB/J010510/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- MH082441/MH/NIMH NIH HHS/ -- R01 DA017204/DA/NIDA NIH HHS/ -- R01 MH061887/MH/NIMH NIH HHS/ -- U19 MH082441/MH/NIMH NIH HHS/ -- WT 083481/Wellcome Trust/United Kingdom -- England -- Nature. 2012 Dec 13;492(7428):215-20. doi: 10.1038/nature11691.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Automation ; Drug Delivery Systems ; *Drug Design ; Female ; *Ligands ; Male ; Mice ; Mice, Inbred C57BL ; Models, Theoretical ; Pharmacological Phenomena ; Reproducibility of Results
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: The puromycin-sensitive aminopeptidase (PSA) is thought to contribute to the degradation of enkephalins. Besides being the most abundant aminopeptidase in the brain, PSA is expressed in other organs as well. From a human fetal brain cDNA library, we have isolated cDNA encoding the human PSA (huPSA) protein. The isolated cDNA gave rise to a protein with a molecular mass of 99 kDa. Compared with mouse PSA, homology at the amino acid and cDNA level was 98 and 93%, respectively. Translation of the huPSA was found to be initiated at the second of two possible start codons, as shown by studies with antibodies directed against peptide sequences of both potential N-terminal regions. Northern blot analysis with RNA isolated from different human organs demonstrated that the huPSA transcript is strongest but not exclusively expressed in the brain. Vesicular stomatitis virus epitope-tagged huPSA protein was expressed in HeLa cells and found to be localized in the cytoplasm, especially in the perinuclear region. By in situ hybridization, huPSA transcript could be identified in cortical and cerebellar neurons, whereas glial cells and blood vessels remained negative.
    Type of Medium: Electronic Resource
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