Shared more. Cited more. Safe forever.
    • advanced search
    • submit works
    • about
    • help
    • contact us
    • login
    View Item 
    •   MOspace Home
    • University of Missouri System
    • Missouri Summits
    • Missouri Regional Life Sciences Summit 2010
    • Abstracts (Missouri Regional Life Sciences Summit 2010)
    • View Item
    •   MOspace Home
    • University of Missouri System
    • Missouri Summits
    • Missouri Regional Life Sciences Summit 2010
    • Abstracts (Missouri Regional Life Sciences Summit 2010)
    • View Item
    JavaScript is disabled for your browser. Some features of this site may not work without it.
    advanced searchsubmit worksabouthelpcontact us

    Browse

    All of MOspaceCommunities & CollectionsDate IssuedAuthor/ContributorTitleIdentifierThesis DepartmentThesis AdvisorThesis SemesterThis CollectionDate IssuedAuthor/ContributorTitleIdentifierThesis DepartmentThesis AdvisorThesis Semester

    Statistics

    Most Popular ItemsStatistics by CountryMost Popular AuthorsStatistics by Referrer

    High Resolution Crystal Structure of KD-247, a Humanized Antibody that Inhibits HIV Entry [abstract]

    Kirby, Karen, 1979-
    Moran, Jennifer L.
    Marchand, Bruno
    Yoshimura, Kazuhisa
    Murakami, Toshio
    Matsushita, Shuzo
    Sarafianos, Stefan G.
    View/Open
    [PDF] HighResolutionCrystalStructure [abstract].pdf (21.16Kb)
    Date
    2010-02
    Contributor
    University of Missouri (System)
    Format
    Abstract
    Metadata
    [+] Show full item record
    Abstract
    Highly active antiretroviral therapy (HAART) has been very efficient in reducing the rate of mortality of human immunodeficiency virus type 1 (HIV-1) infected patients. However, resistance to clinically used drugs inevitably develops and impairs the potency of these drugs. There is also no vaccine available to prevent the spread of the virus. Our collaborators, Dr. Shuzo Matsushita and his colleagues have developed a monoclonal antibody, KD-247, that is currently in Phase Ib clinical trials for the treatment of HIV-1 infections. KD-247 blocks virus entry into host cells by binding to the V3 loop of the surface glycoprotein of HIV. It is the first humanized antibody shown to neutralize a wide range of subtype B HIV viruses (Matsushita et al. Hum. Antibodies, 14, 81) and to prevent HIV infection in cell culture and in a chimpanzee model (Eda et al. J. Virol., 80, 5563). KD-247 reacts exclusively with subtype B viruses (Eda et al. J. Virol., 80, 5552). In order to understand the molecular basis of this specificity we have solved the crystal structure of KD-247 at 1.5 Å resolution, the highest resolution structure for any humanized antibody reported to date. The present structure reveals in atomic detail the molecular boundaries of a pocket formed by the antigen-binding region of the antibody. Molecular docking experiments of a pre-existing structure of the V3-loop target at the presumed binding pocket on KD-247 suggest possible molecular interactions involved in HIV resistance to KD-247 and clade B specificity. A G314E V3 loop mutation that has been reported to confer resistance to KD-247 (Yoshimura et al., AIDS 20, 2065) appears to result in steric interactions between the tip of the V3 loop and residues of the heavy chain of KD-247. Further, Arg315, a residue critical for clade B specificity, appears to form extensive interactions with multiple residues of KD-247. Analysis of these interactions has provided insights into the design of second-generation antibodies with broader subtype specificity and improved ability to evade resistance mutations. This work is a product of collaborations between the University of Missouri and researchers at Kumamoto University, an academic institution in Japan, and the Chemo-Sero-Therapeutic Research Institute, an industrial partner in Japan, working to commercialize the antibody and further its progress in clinical trials.
    URI
    http://hdl.handle.net/10355/6118
    Part of
    Abstracts (Missouri Regional Life Sciences Summit 2010)
    Collections
    • Abstracts (Missouri Regional Life Sciences Summit 2010)
    • Molecular Microbiology and Immunology presentations (MU)

    Send Feedback
    hosted by University of Missouri Library Systems
     

     


    Send Feedback
    hosted by University of Missouri Library Systems