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New Approach for Inhibition of HIV Entry: Modifying CD4 Binding Sites by Thiolated Pyrimidine Derivatives

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Pathology & Oncology Research

Abstract

Thiolated pyrimidine derivatives have been synthetized and their antiretroviral effect against human immunodeficiency virus type 1 (HIV-1IIIB) and HIV-1 chimeric pseudovirions have been quantitatively determined in cell-based viral infectivity assays including syncytium inhibition assay as well as a single-cycle viral infection assay on HeLaCD4-LTR/ß-gal cells. Pseudotype virions prepared bearing HIV-1 envelope preference for CCR5 coreceptor, CXCR4 coreceptor or for both, respectively, with a HIV-1 core containing luciferase reporter gene were able to infect susceptible cells but are replication defective so unable to replicate in the cells . Data indicate that thiolated pyrimidine derivatives inhibited effectively virally induced cell fusion in vitro as well as infectivity of primary HIV-1IIIB strain and HIV-1 pseudovirions using chemokine receptors CCR5 or CXCR4 or both for virus entry a dose dependent manner. Inhibition was selective, depended on the pseudovirus coreceptor preference. Our results suggest that some of these sulfur containing pyrimidines interact with redoxactive -SH groups required for successful HIV entry, including a redox active disulfide in the CD4 molecule as well as -SH groups in HIV viral envelope gp120. This mode of action is unique representing a new class of potential HIV entry inhibitors.

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Acknowledgments

This work was supported by OTKA 81367 Grant from the National Science Foundation of Hungary

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Authors and Affiliations

  1. Institute of Medical Microbiology, Semmelweis University, Budapest, Hungary

    Szilvia Kanizsai, József Ongrádi & Károly Nagy

  2. Department Biochemistry and Molecular Biology, University of Debrecen, Debrecen, Hungary

    János Aradi

Authors
  1. Szilvia Kanizsai
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  2. József Ongrádi
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  3. János Aradi
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  4. Károly Nagy
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Correspondence to Károly Nagy.

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The authors declare there is no conflict of interest in this work.

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Kanizsai, S., Ongrádi, J., Aradi, J. et al. New Approach for Inhibition of HIV Entry: Modifying CD4 Binding Sites by Thiolated Pyrimidine Derivatives. Pathol. Oncol. Res. 22, 617–623 (2016). https://doi.org/10.1007/s12253-016-0044-y

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  • DOI: https://doi.org/10.1007/s12253-016-0044-y

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