New Approach for Inhibition of HIV Entry: Modifying CD4 Binding Sites by Thiolated Pyrimidine Derivatives
- 218 Downloads
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.
KeywordsHIV entry Thiolated pyrimidine derivatives HIV-1 pseudotypes Redox processes CD4
This work was supported by OTKA 81367 Grant from the National Science Foundation of Hungary
Compliance with ethical standards
Conflict of Interest
The authors declare there is no conflict of interest in this work.
- 1.Kaplan JE, Hanson D, Dworkin MS, Frederick T, Bertolli J, Lindegren ML, Holmberg S, Jones JL (2000) Epidemiology of human immunodeficiency virus-associated opportunistic infectiopns in the United States in the era of highly active antiretroviral therapy. Clin Infect Dis 30:S5–S14CrossRefPubMedGoogle Scholar
- 9.Kemény B, Nagy K, Horváth A (2000) CCR5 and SDF1 gene polymorphism in HIV-infected and healthy individuals in Hungary. Hung Venerol Arch IV(2–3):89–92Google Scholar
- 16.Nagy K (2007) HIV pseudovirions assay for coreceptor selection and entry fitness. Proc. HIV correlates (Ed:Fust G) p12., BudapestGoogle Scholar