In vitro anti-human immunodeficiency virus activity of 2',3'-dideoxynucleosides and their effect on clonal growth of hemopoietic cells from human bone marrow.
Seven 2',3'-dideoxynucleosides synthesized by substitution of nucleosides using nucleoside deoxyribosyltransferase from Lactobacillus leichmanii were tested for their anti-human immunodeficiency virus (HIV) activity. Two of them, including 2,6-diaminopurine-2',3'-dideoxyriboside (DAPDDR) and 6-chlorpurine-2',3'-dideoxyriboside (CPDDR) demonstrated high antiviral activity against several strains of HIV-1 and one strain of HIV-2. The selectivity index of the drugs (SI; ratio of the drug concentration required for 50% of cell killing to drug concentration required to inhibit 50% of virus-induced cell killing) was established by application of tetrazolium (MTT) colorimetric assay. SI ranged for different HIV strains from 501 to 850 and from 60 to 118 for DAPDDR and CPDDR, respectively. Both DAPDDR and CPDDR retained their antiviral activity against HIV-1 strain D148/88 which was resistant to Zidovudine (3'-azido-3'-deoxythymidine, AZT). Assays for clonal growth of human bone marrow cells in semisolid fibrin clot culture medium demonstrated that DAPDDR possesses significantly lower inhibitory activity for erythroid (BFU-E), multipotent (GEMM-CFC) and granulocyte-monocyte (GM-CFC) bone marrow progenitor cells than CPDDR or AZT. These results suggest that DAPDDR is a nucleoside analog which should be further tested as an anti-HIV compound especially in combination with other anti-retroviral drugs.
Cinatl
J
J
Centre of Hygiene, Johann Wolfgang Goethe-University, Frankfurt/Main, Fed. Rep. of Germany.
Cinatl
J
J
Rabenau
H
H
Gümbel
H
H
Doerr
H W
HW
D000998:Antiviral Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001853:Bone Marrow / Q000187:drug effects; D001854:Bone Marrow Cells; D002460:Cell Line; D002999:Clone Cells / Q000187:drug effects; D003124:Colorimetry; D015224:Dideoxynucleosides / Q000138:chemical synthesis / Q000494:pharmacology*; D004351:Drug Resistance; D015497:HIV-1 / Q000187:drug effects*; D015498:HIV-2 / Q000187:drug effects*; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006801:Humans; D013234:Stem Cells / Q000187:drug effects; D013778:Tetrazolium Salts; D013844:Thiazoles; D015215:Zidovudine / Q000494:pharmacology
D000998:Antiviral Agents; D015224:Dideoxynucleosides; D013778:Tetrazolium Salts; D013844:Thiazoles; D015215:Zidovudine; C022616:thiazolyl blue