Inhibitory Effects of Small-Molecule CCR5 Antagonists on Human Immunodeficiency Virus Type 1 Envelope-Mediated Membrane Fusion and Viral Replication
| Autor: | Mitsuru Shiraishi, Masanori Baba, Hiroshi Miyake, Jun-ichi Fujisawa, Katsunori Takashima, Naoyuki Kanzaki, Rika A. Furuta, Yuji Iizawa, Kenji Okonogi |
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| Rok vydání: | 2001 |
| Předmět: |
Anti-HIV Agents
T-Lymphocytes viruses T cell CCR5 receptor antagonist Biology Virus Replication Antiviral Agents Membrane Fusion Virus Viral Envelope Proteins medicine Humans Pharmacology (medical) Chemokine CCL5 Pharmacology Reporter gene Effector HEK 293 cells virus diseases Lipid bilayer fusion Amides Molecular biology Quaternary Ammonium Compounds Infectious Diseases medicine.anatomical_structure Viral replication CCR5 Receptor Antagonists Gene Products tat HIV-1 tat Gene Products Human Immunodeficiency Virus HeLa Cells |
| Zdroj: | Antimicrobial Agents and Chemotherapy. 45:3538-3543 |
| ISSN: | 1098-6596 0066-4804 |
| DOI: | 10.1128/aac.45.12.3538-3543.2001 |
| Popis: | We established a human immunodeficiency virus type 1 (HIV-1) envelope (Env)-mediated membrane fusion assay and examined the small-molecule CCR5 antagonist TAK-779 and its derivatives for their inhibitory effects on HIV-1 Env-mediated membrane fusion and viral replication. The membrane fusion assay is based on HIV-1 long terminal repeat-directed β- d -galactosidase reporter gene expression in CD4- and CCR5-expressed HeLa (MAGI-CCR5) cells after cocultivation with effector 293T cells expressing HIV-1 Env. Inhibition of HIV-1 replication was also determined in MAGI-CCR5 cells infected with the corresponding cell-free HIV-1. TAK-779 effectively suppressed R5 HIV-1 (strain JR-FL) Env-mediated membrane fusion as well as viral replication. Its 50% inhibitory concentrations (IC 50 s) for membrane fusion and viral replication were 0.87 ± 0.11 and 1.4 ± 0.1 nM, respectively. These values corresponded well to the IC 50 for 125 I-RANTES (regulated on activation, T cell expressed, and secreted) binding to CCR5 (1.4 nM). The inhibitory effects of 18 TAK-779 derivatives on membrane fusion differed from one compound to another. However, there was a close correlation among their inhibitory effects on membrane fusion, viral replication, and RANTES binding. The correlation coefficient between their IC 50 s for membrane fusion and viral replication was 0.881. Furthermore, since this assay depends on Env expressed in the effector cells, it is also applicable to the evaluation of CXCR4 antagonists. These results indicate that the HIV-1 Env-mediated membrane fusion assay is a useful tool for the evaluation of entry inhibitors. |
| Databáze: | OpenAIRE |
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