title: New Approach for Inhibition of HIV Entry: Modifying CD4 Binding Sites by Thiolated Pyrimidine Derivatives.
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.
authors: Institute of Medical Microbiology, Semmelweis University, Budapest, Hungary.
authors: Szilvia
authors: S
authors: Kanizsai
authors: Institute of Medical Microbiology, Semmelweis University, Budapest, Hungary.
authors: József
authors: J
authors: Ongrádi
authors: Department Biochemistry and Molecular Biology, University of Debrecen, Debrecen, Hungary.
authors: János
authors: J
authors: Aradi
authors: Institute of Medical Microbiology, Semmelweis University, Budapest, Hungary. nagy.karoly@med.semmelweis-univ.hu.
authors: Károly
authors: K
authors: Nagy
mesh_terms: D001665:Binding Sites / Q000187:drug effects*; D015704:CD4 Antigens / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D057809:HEK293 Cells; D015699:HIV Envelope Protein gp120 / Q000378:metabolism; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D011743:Pyrimidines / Q000494:pharmacology*; D019713:Receptors, CCR5 / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism; D013457:Sulfur Compounds / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects
chemical_list: C584933:CCR5 protein, human; D015704:CD4 Antigens; C527276:CXCR4 protein, human; D015699:HIV Envelope Protein gp120; D011743:Pyrimidines; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D013457:Sulfur Compounds
keywords: CD4; HIV entry; HIV-1 pseudotypes; Redox processes; Thiolated pyrimidine derivatives