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GPG-NH2 acts via the metabolite alpha HGA to target HIV-1 Env to the ER-associated protein degradation pathway
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
2010 (English)In: Retrovirology, ISSN 1742-4690, Vol. 7, 20- p.Article in journal (Refereed) Published
Abstract [en]

Background: The synthetic peptide glycyl-prolyl-glycine amide (GPG-NH2) was previously shown to abolish the ability of HIV-1 particles to fuse with the target cells, by reducing the content of the viral envelope glycoprotein (Env) in progeny HIV-1 particles. The loss of Env was found to result from GPG-NH2 targeting the Env precursor protein gp160 to the ER-associated protein degradation (ERAD) pathway during its maturation. However, the antiviral effect of GPG-NH2 has been shown to be mediated by its metabolite alpha-hydroxy-glycineamide (alpha HGA), which is produced in the presence of fetal bovine serum, but not human serum. In accordance, we wanted to investigate whether the targeting of gp160 to the ERAD pathway by GPG-NH2 was attributed to its metabolite alpha HGA. Results: In the presence of fetal bovine serum, GPG-NH2, its intermediary metabolite glycine amide (G-NH2), and final metabolite alpha HGA all induced the degradation of gp160 through the ERAD pathway. However, when fetal bovine serum was replaced with human serum only aHGA showed an effect on gp160, and this activity was further shown to be completely independent of serum. This indicated that GPG-NH2 acts as a pro-drug, which was supported by the observation that it had to be added earlier to the cell cultures than alpha HGA to induce the degradation of gp160. Furthermore, the substantial reduction of Env incorporation into HIV-1 particles that occurs during GPG-NH2 treatment was also achieved by treating HIV-1 infected cells with alpha HGA. Conclusions: The previously observed specificity of GPG-NH2 towards gp160 in HIV-1 infected cells, resulting in the production of Env (gp120/gp41) deficient fusion incompetent HIV-1 particles, was most probably due to the action of the GPG-NH2 metabolite alpha HGA.

Place, publisher, year, edition, pages
2010. Vol. 7, 20- p.
National Category
Medical and Health Sciences Natural Sciences
URN: urn:nbn:se:uu:diva-137104DOI: 10.1186/1742-4690-7-20ISI: 000276220700001OAI: oai:DiVA.org:uu-137104DiVA: diva2:377914
Available from: 2010-12-15 Created: 2010-12-15 Last updated: 2010-12-15Bibliographically approved

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