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Thermodynamic instability of viral proteins is a pathogen-associated molecular pattern targeted by human defensins
Ohio State Univ, Dept Chem & Biochem, Columbus, OH 43210 USA..
Ohio State Univ, Ctr Retroviral Res, Columbus, OH 43210 USA.;Ohio State Univ, Coll Pharm, 500 W 12Th Ave, Columbus, OH 43210 USA..
Ohio State Univ, Ctr Retroviral Res, Columbus, OH 43210 USA.;Ohio State Univ, Coll Pharm, 500 W 12Th Ave, Columbus, OH 43210 USA..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
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2016 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, 32499Article in journal (Refereed) Published
Abstract [en]

Human defensins are innate immune defense peptides with a remarkably broad repertoire of anti-pathogen activities. In addition to modulating immune response, inflammation, and angiogenesis, disintegrating bacterial membranes, and inactivating bacterial toxins, defensins are known to intercept various viruses at different stages of their life cycles, while remaining relatively benign towards human cells and proteins. Recently we have found that human defensins inactivate proteinaceous bacterial toxins by taking advantage of their low thermodynamic stability and acting as natural "anti-chaperones", i.e. destabilizing the native conformation of the toxins. In the present study we tested various proteins produced by several viruses (HIV-1, PFV, and TEV) and found them to be susceptible to destabilizing effects of human alpha-defensins HNP-1 and HD-5 and the synthetic theta-defensin RC-101, but not beta-defensins hBD-1 and hBD-2 or structurally related plant-derived peptides. Defensin-induced unfolding promoted exposure of hydrophobic groups otherwise confined to the core of the viral proteins. This resulted in precipitation, an enhanced susceptibility to proteolytic cleavage, and a loss of viral protein activities. We propose, that defensins recognize and target a common and essential physico-chemical property shared by many bacterial toxins and viral proteins - the intrinsically low thermodynamic protein stability.

Place, publisher, year, edition, pages
2016. Vol. 6, 32499
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-303735DOI: 10.1038/srep32499ISI: 000382370300002PubMedID: 27581352OAI: oai:DiVA.org:uu-303735DiVA: diva2:973920
Funder
NIH (National Institute of Health), R01 AI110310; R01 AI072732
Available from: 2016-09-23 Created: 2016-09-23 Last updated: 2017-11-21Bibliographically approved

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