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Mechanism of Adenovirus Neutralization by Human a-Defensins - Study

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  • Mechanism of Adenovirus Neutralization by Human a-Defensins - Study

    Wed Jan 16 2008

    Scripps Research Scientists: Naturally Occurring Peptide Inhibits Common Viral Infection;

    Study Points Toward Potential New Antiviral Therapeutic Strategies

    LA JOLLA, Calif., Jan. 16 (AScribe Newswire) -- Scientists at The Scripps Research Institute have found that a naturally occurring peptide known for its antibacterial action can also inhibit viral infection.

    The study was published in the January 17, 2008 edition of the journal Cell Host & Microbe.

    The new study shows that defensins, short antimicrobial peptides that disrupt bacterial membranes and prevent bacterial invasion, use a separate mechanism to ward off adenovirus. Adenovirus is a group of viruses responsible for a number of respiratory diseases as well as infection of the stomach and intestine, eyes, bladder, and skin. While these infections are generally mild, they can turn fatal in patients with compromised immune systems.

    "Our study reveals a previously unrecognized mechanism of antiviral action for defensins," said Glen Nemerow, a Scripps Research professor of immunology whose laboratory conducted the new study. "This discovery suggests one potential way to block adenovirus infection effectively with a small molecule compound. Because defensins are natural peptides, this approach might also provide a novel way to design drugs that would be well tolerated."

    The new study found that two forms of human a-defensins (expressed in specific types of white blood cells, epithelial cells of the small intestine, the female genitourinary tract, and air passages) had potent anti-adenoviral activity in cell culture. When added at the beginning of a 60-minute viral incubation period, defensins achieved 96 percent adenovirus inhibition at very low concentrations. At higher doses, defensins stopped virtually all viral infection activity.

    Adenovirus cell entry involves close interaction with host cell receptors that mediate attachment, internalization, and finally penetration of the endosomal membrane-compartments within the cell. The Scripps Research scientists found that the defensins blocked infection by binding to and stabilizing the virus capsid-the protein shell that holds the viral nucleic acid-and preventing partial uncoating of the virus, which marks the start of the infection process.

    "Defensins inhibit the release of an internal viral protein called pVI, which is required for endosomal membrane penetration during cell entry," said Jason Smith, first author of the study. "This results in an accumulation of infectious virions in intracellular endosomes and lysosomes, where they are eventually destroyed. This is the first time this mechanism has been identified."

    Smith also noted that until now most research has focused on enveloped viruses such as hepatitis C and HIV. Adenoviruses, in contrast, are nonenveloped or naked viruses; they lack an outer coating of lipoprotein. Other nonenveloped viruses include polio, cold viruses, and human papillomavirus.

    "Our study suggests that this may be a general mechanism for inhibition of nonenveloped virus infections," Nemerow added. "It's tempting to speculate that these and other antimicrobial peptides may serve as valuable tools with which to reveal the precise pathways of virus entry into host cells."

    The study, "Mechanism of Adenovirus Neutralization by Human a-Defensins," was supported by the National Institutes of Health.

    About The Scripps Research Institute

    The Scripps Research Institute is one of the world's largest independent, non-profit biomedical research organizations, at the forefront of basic biomedical science that seeks to comprehend the most fundamental processes of life. Scripps Research is internationally recognized for its discoveries in immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune, cardiovascular, and infectious diseases, and synthetic vaccine development.

    Established in its current configuration in 1961, it employs approximately 3,000 scientists, postdoctoral fellows, scientific and other technicians, doctoral degree graduate students, and administrative and technical support personnel. Scripps Research is headquartered in La Jolla, California. It also includes Scripps Florida, whose researchers focus on basic biomedical science, drug discovery, and technology development. Currently operating from temporary facilities in Jupiter, Scripps Florida will move to its permanent campus in 2009.

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    CONTACT: Keith McKeown, SRI Media Relations, 858-784-8134,
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