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Griffithsin tandemers: flexible and potent lectin inhibitors of the human immunodeficiency virus.

ABSTRACT: The lectin griffithsin (GRFT) is a potent antiviral agent capable of prevention and treatment of infections caused by a number of enveloped viruses and is currently under development as an anti-HIV microbicide. In addition to its broad antiviral activity, GRFT is stable at high temperature and at a broad pH range, displays little toxicity and immunogenicity, and is amenable to large-scale manufacturing. Native GRFT is a domain-swapped homodimer that binds to viral envelope glycoproteins and has displayed mid-picomolar activity in cell-based anti-HIV assays. Previously, we have engineered and analyzed several monomeric forms of this lectin (mGRFT) with anti-HIV EC50 values ranging up to 323 nM. Based on our previous analysis of mGRFT, we hypothesized that the orientation and spacing of the carbohydrate binding domains GRFT were key to its antiviral activity.Here we present data on engineered tandem repeats of mGRFT (mGRFT tandemers) with antiviral activity at concentrations as low as one picomolar in whole-cell anti-HIV assays. mGRFT tandemers were analyzed thermodynamically, both individually and in complex with HIV-1 gp120. We also demonstrate by dynamic light scattering and cryo-electron microscopy that mGRFT tandemers do not aggregate HIV virions. This establishes that, although the intra-virion crosslinking of HIV envelope glycoproteins is likely integral to their activity, the antiviral activity of these lectins is not due to virus aggregation caused by inter-virion crosslinking.The engineered tandemer constructs of mGRFT may provide novel and powerful agents for prevention of infection by HIV and other enveloped viruses.

SUBMITTER: Moulaei T

PROVIDER: S-EPMC4419512 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Griffithsin tandemers: flexible and potent lectin inhibitors of the human immunodeficiency virus.

Moulaei Tinoush T Alexandre Kabamba B KB Shenoy Shilpa R SR Meyerson Joel R JR Krumpe Lauren Rh LR Constantine Brian B Wilson Jennifer J Buckheit Robert W RW McMahon James B JB Subramaniam Sriram S Wlodawer Alexander A O'Keefe Barry R BR

Retrovirology 20150123

<h4>Background</h4>The lectin griffithsin (GRFT) is a potent antiviral agent capable of prevention and treatment of infections caused by a number of enveloped viruses and is currently under development as an anti-HIV microbicide. In addition to its broad antiviral activity, GRFT is stable at high temperature and at a broad pH range, displays little toxicity and immunogenicity, and is amenable to large-scale manufacturing. Native GRFT is a domain-swapped homodimer that binds to viral envelope gly ...[more]

PMID: 25613831

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Griffithsin tandemers: flexible and potent lectin inhibitors of the human immunodeficiency virus.

Publications

Griffithsin tandemers: flexible and potent lectin inhibitors of the human immunodeficiency virus.

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