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  • 1
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    Structure-based design of non-natural amino-acid inhibitors of amyloid fibril formation (2011)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2011-06-17
    Description: Many globular and natively disordered proteins can convert into amyloid fibrils. These fibrils are associated with numerous pathologies as well as with normal cellular functions, and frequently form during protein denaturation. Inhibitors of pathological amyloid fibril formation could be useful in the development of therapeutics, provided that the inhibitors were specific enough to avoid interfering with normal processes. Here we show that computer-aided, structure-based design can yield highly specific peptide inhibitors of amyloid formation. Using known atomic structures of segments of amyloid fibrils as templates, we have designed and characterized an all-D-amino-acid inhibitor of the fibril formation of the tau protein associated with Alzheimer's disease, and a non-natural L-amino-acid inhibitor of an amyloid fibril that enhances sexual transmission of human immunodeficiency virus. Our results indicate that peptides from structure-based designs can disrupt the fibril formation of full-length proteins, including those, such as tau protein, that lack fully ordered native structures. Because the inhibiting peptides have been designed on structures of dual-beta-sheet 'steric zippers', the successful inhibition of amyloid fibril formation strengthens the hypothesis that amyloid spines contain steric zippers.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4073670/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4073670/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sievers, Stuart A -- Karanicolas, John -- Chang, Howard W -- Zhao, Anni -- Jiang, Lin -- Zirafi, Onofrio -- Stevens, Jason T -- Munch, Jan -- Baker, David -- Eisenberg, David -- P50 AG016570/AG/NIA NIH HHS/ -- R01 AG029430/AG/NIA NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Jun 15;475(7354):96-100. doi: 10.1038/nature10154.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biological Chemistry, Howard Hughes Medical Institute, UCLA, Box 951970, Los Angeles, California 90095-1570, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21677644" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Amino Acids/*chemistry/*pharmacology ; Amyloid/*antagonists & inhibitors/*chemistry/metabolism ; Amyloid beta-Peptides/antagonists & inhibitors/chemistry/metabolism ; Computer-Aided Design ; *Drug Design ; HIV Infections/virology ; Hydrogen Bonding ; Kinetics ; Models, Molecular ; Peptides/*chemistry/*pharmacology ; Polylysine/pharmacology ; Protein Conformation ; tau Proteins/antagonists & inhibitors
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 2
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    Therapeutic efficacy of potent neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys (2013)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2013-11-01
    Description: Human immunodeficiency virus type 1 (HIV-1)-specific monoclonal antibodies with extraordinary potency and breadth have recently been described. In humanized mice, combinations of monoclonal antibodies have been shown to suppress viraemia, but the therapeutic potential of these monoclonal antibodies has not yet been evaluated in primates with an intact immune system. Here we show that administration of a cocktail of HIV-1-specific monoclonal antibodies, as well as the single glycan-dependent monoclonal antibody PGT121, resulted in a rapid and precipitous decline of plasma viraemia to undetectable levels in rhesus monkeys chronically infected with the pathogenic simian-human immunodeficiency virus SHIV-SF162P3. A single monoclonal antibody infusion afforded up to a 3.1 log decline of plasma viral RNA in 7 days and also reduced proviral DNA in peripheral blood, gastrointestinal mucosa and lymph nodes without the development of viral resistance. Moreover, after monoclonal antibody administration, host Gag-specific T-lymphocyte responses showed improved functionality. Virus rebounded in most animals after a median of 56 days when serum monoclonal antibody titres had declined to undetectable levels, although, notably, a subset of animals maintained long-term virological control in the absence of further monoclonal antibody infusions. These data demonstrate a profound therapeutic effect of potent neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys as well as an impact on host immune responses. Our findings strongly encourage the investigation of monoclonal antibody therapy for HIV-1 in humans.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4017780/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4017780/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Barouch, Dan H -- Whitney, James B -- Moldt, Brian -- Klein, Florian -- Oliveira, Thiago Y -- Liu, Jinyan -- Stephenson, Kathryn E -- Chang, Hui-Wen -- Shekhar, Karthik -- Gupta, Sanjana -- Nkolola, Joseph P -- Seaman, Michael S -- Smith, Kaitlin M -- Borducchi, Erica N -- Cabral, Crystal -- Smith, Jeffrey Y -- Blackmore, Stephen -- Sanisetty, Srisowmya -- Perry, James R -- Beck, Matthew -- Lewis, Mark G -- Rinaldi, William -- Chakraborty, Arup K -- Poignard, Pascal -- Nussenzweig, Michel C -- Burton, Dennis R -- AI055332/AI/NIAID NIH HHS/ -- AI060354/AI/NIAID NIH HHS/ -- AI078526/AI/NIAID NIH HHS/ -- AI084794/AI/NIAID NIH HHS/ -- AI095985/AI/NIAID NIH HHS/ -- AI096040/AI/NIAID NIH HHS/ -- AI100148/AI/NIAID NIH HHS/ -- AI10063/AI/NIAID NIH HHS/ -- AI100663/AI/NIAID NIH HHS/ -- P01 AI100148/AI/NIAID NIH HHS/ -- P40 OD012217/OD/NIH HHS/ -- P51 RR000168/RR/NCRR NIH HHS/ -- R01 AI084794/AI/NIAID NIH HHS/ -- R37 AI055332/AI/NIAID NIH HHS/ -- R56 AI091514/AI/NIAID NIH HHS/ -- T32 AI007387/AI/NIAID NIH HHS/ -- U19 AI066305/AI/NIAID NIH HHS/ -- U19 AI078526/AI/NIAID NIH HHS/ -- U19 AI095985/AI/NIAID NIH HHS/ -- U19 AI096040/AI/NIAID NIH HHS/ -- UM1 AI100663/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Nov 14;503(7475):224-8. doi: 10.1038/nature12744. Epub 2013 Oct 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA [2] Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts 02139, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24172905" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antibodies, Monoclonal/*therapeutic use ; Antibodies, Neutralizing/*therapeutic use ; DNA, Viral/blood ; HIV Antibodies/immunology ; HIV-1/*immunology ; Macaca mulatta ; Simian Acquired Immunodeficiency Syndrome/*therapy ; Simian Immunodeficiency Virus/*physiology ; T-Lymphocytes/immunology ; Viremia/therapy
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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