Critical role of reverse transcriptase in the inhibitory mechanism of CNI-H0294 on HIV-1 nuclear translocation
| Autor: | Günter Blobel, Anthony Cerami, May-Ann Lee, Michael Bukrinsky, Sridhar Pennathur, Serguei Popov, Michael Rexach, Larisa Dubrovsky, Omar K. Haffar, Peter C. Ulrich, Yousef Al-Abed, Peter J. Tonge |
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| Jazyk: | angličtina |
| Rok vydání: | 1996 |
| Předmět: |
alpha Karyopherins
Virus Integration Genome Viral Biology Virus Replication Antiviral Agents Monocytes Structure-Activity Relationship Viral Proteins medicine Structure–activity relationship Humans Nuclear protein Cells Cultured Karyopherin chemistry.chemical_classification Cell Nucleus Multidisciplinary Virion Nuclear Proteins Alpha Karyopherins Molecular biology Reverse transcriptase HIV Reverse Transcriptase Cell nucleus medicine.anatomical_structure Pyrimidines Viral replication chemistry HIV-1 Nuclear localization sequence Research Article |
| Popis: | HIV-1 replication requires the translocation of viral genome into the nucleus of a target cell. We recently reported the synthesis of an arylene bis(methyl ketone) compound (CNI-H0294) that inhibits nuclear targeting of the HIV-1 genome and thus HIV-1 replication in monocyte cultures. Here we demonstrate that CNI-H0294 inhibits nuclear targeting of HIV-1-derived preintegration complexes by inactivating the nuclear localization sequence of the HIV-1 matrix antigen in a reaction that absolutely requires reverse transcriptase. This drug/reverse transcriptase interaction defines the specificity of its antiviral effect and is most likely mediated by the pyrimidine side-chain of CNI-H0294. After binding to reverse transcriptase, the carbonyl groups of CNI-H0294 react with the nuclear localization sequence of matrix antigen and prevent its binding to karyopherin alpha, the cellular receptor for nuclear localization sequences that carries proteins into the nucleus. Our results provide a basis for the development of a novel class of compounds that inhibit nuclear translocation and that can, in principle, be modified to target specific infectious agents. |
| Databáze: | OpenAIRE |
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