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The Membrane-Active Phytopeptide Cycloviolacin O2 Simultaneously Targets HIV-1-infected Cells and Infectious Viral Particles to Potentiate the Efficacy of Antiretroviral Drugs

1
Department of Biology, Division of Science, Technology, Engineering and Mathematics, Dillard University, New Orleans, LA 70122, USA
2
Department of Pharmacology, Tulane University Medical Center, New Orleans, LA 70112, USA
3
Department of Health and Biomedical Sciences, University of Texas Rio Grande Valley, Brownsville, TX 78520, USA
4
Department of Medicinal Chemistry, Uppsala University, 751 23 Uppsala, Sweden
5
Department of Biochemistry and Molecular Biology, Tulane University Medical Center, New Orleans, LA 70112, USA
6
Tulane National Primate Research Center, Covington, LA 70112, USA
*
Author to whom correspondence should be addressed.
Medicines 2019, 6(1), 33; https://doi.org/10.3390/medicines6010033
Received: 21 January 2019 / Revised: 22 February 2019 / Accepted: 24 February 2019 / Published: 28 February 2019
(This article belongs to the Special Issue Plant-Derived Medicines and Biological Activity Evaluation)
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Abstract

Background: Novel strategies to increase the efficacy of antiretroviral (ARV) drugs will be of crucial importance. We hypothesize that membranes of HIV-1-infected cells and enveloped HIV-1 particles may be preferentially targeted by the phytopeptide, cycloviolacin O2 (CyO2) to significantly enhance ARV efficacy. Methods: Physiologically safe concentrations of CyO2 were determined via red blood cell (RBC) hemolysis. SYTOX-green dye-uptake and radiolabeled saquinavir (3H-SQV) uptake assays were used to measure pore-formation and drug uptake, respectively. ELISA, reporter assays and ultracentrifugation were conducted to analyze the antiviral efficacy of HIV-1 protease and fusion inhibitors alone and co-exposed to CyO2. Results: CyO2 concentrations below 0.5 μM did not show substantial hemolytic activity, yet these concentrations enabled rapid pore-formation in HIV-infected T-cells and monocytes and increased drug uptake. ELISA for HIV-1 p24 indicated that CyO2 enhances the antiviral efficacy of both SQV and nelfinavir. CyO2 (< 0.5 μM) alone decreases HIV-1 p24 production, but it did not affect the transcription regulatory function of the HIV-1 long terminal repeat (LTR). Ultracentrifugation studies clearly showed that CyO2 exposure disrupted viral integrity and decreased the p24 content of viral particles. Furthermore, direct HIV-1 inactivation by CyO2 enhanced the efficacy of enfuvirtide. Conclusions: The membrane-active properties of CyO2 may help suppress viral load and augment antiretroviral drug efficacy. View Full-Text
Keywords: cyclotides; cycloviolacin O2; CyO2; HIV-1; protease inhibitors; fusion inhibitors; antiretroviral drugs cyclotides; cycloviolacin O2; CyO2; HIV-1; protease inhibitors; fusion inhibitors; antiretroviral drugs
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Gerlach, S.L.; Chandra, P.K.; Roy, U.; Gunasekera, S.; Göransson, U.; Wimley, W.C.; Braun, S.E.; Mondal, D. The Membrane-Active Phytopeptide Cycloviolacin O2 Simultaneously Targets HIV-1-infected Cells and Infectious Viral Particles to Potentiate the Efficacy of Antiretroviral Drugs. Medicines 2019, 6, 33.

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