Synthesis of a photoaffinity analog of 3'-azidothymidine, 5-azido-3'-azido-2',3'-dideoxyuridine. Interactions with herpesvirus thymidine kinase and cellular enzymes. 1995

F Mao, and T M Rechtin, and R Jones, and A A Cantu, and L S Anderson, and A Radominska, and M P Moyer, and R R Drake
Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock 72205, USA.

Long term administration of 3'-azidothymidine (AZT) for the treatment of AIDS has led to detrimental clinical side effects in some patients, the biochemical causes of which are still being delineated. Base-substituted, azido-nucleotide photoaffinity analogs have routinely proven to be effective tools for identifying and characterizing nucleotide-utilizing enzymes. Therefore, we have synthesized 5-azido-3'-azido-2',3'-dideoxyuridine, which is a potential photoaffinity analog of two human immunodeficiency virus drugs, AZT and 3'azido-2',3'-dideoxyuridine. A partially purified herpes simplex virus type 1 thymidine kinase and [gamma-32P]ATP were used to make an AZT monophosphate analog, [32P]5-azido-3'-azido-2',3'-dideoxyuridine monophosphate. The photoaffinity properties of this analog were initially tested with herpes simplex virus type 1 thymidine kinase. Photoaffinity labeling of this enzyme was saturable (half-maximal, 30 microM) and could be specifically inhibited by AZT, AZT monophosphate, thymidine, and thymidine monophosphate. Photolabeling of rat liver microsomal membranes was also done, and several membrane proteins that interact with AZT monophosphate were identified. The antiviral and cytotoxic activities of 5-azido-3'-azido-2',3'-dideoxyuridine were determined using human immunodeficiency virus, type 1 strain IIIB and an AZT drug-resistant strain in human T lymphocyte H9 cells.

UI MeSH Term Description Entries
D008862 Microsomes, Liver Closed vesicles of fragmented endoplasmic reticulum created when liver cells or tissue are disrupted by homogenization. They may be smooth or rough. Liver Microsomes,Liver Microsome,Microsome, Liver
D006678 HIV Human immunodeficiency virus. A non-taxonomic and historical term referring to any of two species, specifically HIV-1 and/or HIV-2. Prior to 1986, this was called human T-lymphotropic virus type III/lymphadenopathy-associated virus (HTLV-III/LAV). From 1986-1990, it was an official species called HIV. Since 1991, HIV was no longer considered an official species name; the two species were designated HIV-1 and HIV-2. AIDS Virus,HTLV-III,Human Immunodeficiency Viruses,Human T-Cell Lymphotropic Virus Type III,Human T-Lymphotropic Virus Type III,LAV-HTLV-III,Lymphadenopathy-Associated Virus,Acquired Immune Deficiency Syndrome Virus,Acquired Immunodeficiency Syndrome Virus,Human Immunodeficiency Virus,Human T Cell Lymphotropic Virus Type III,Human T Lymphotropic Virus Type III,Human T-Cell Leukemia Virus Type III,Immunodeficiency Virus, Human,Immunodeficiency Viruses, Human,Virus, Human Immunodeficiency,Viruses, Human Immunodeficiency,AIDS Viruses,Human T Cell Leukemia Virus Type III,Lymphadenopathy Associated Virus,Lymphadenopathy-Associated Viruses,Virus, AIDS,Virus, Lymphadenopathy-Associated,Viruses, AIDS,Viruses, Lymphadenopathy-Associated
D000345 Affinity Labels Analogs of those substrates or compounds which bind naturally at the active sites of proteins, enzymes, antibodies, steroids, or physiological receptors. These analogs form a stable covalent bond at the binding site, thereby acting as inhibitors of the proteins or steroids. Affinity Labeling Reagents,Labeling Reagents, Affinity,Labels, Affinity,Reagents, Affinity Labeling
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D000998 Antiviral Agents Agents used in the prophylaxis or therapy of VIRUS DISEASES. Some of the ways they may act include preventing viral replication by inhibiting viral DNA polymerase; binding to specific cell-surface receptors and inhibiting viral penetration or uncoating; inhibiting viral protein synthesis; or blocking late stages of virus assembly. Antiviral,Antiviral Agent,Antiviral Drug,Antivirals,Antiviral Drugs,Agent, Antiviral,Agents, Antiviral,Drug, Antiviral,Drugs, Antiviral
D013937 Thymidine Kinase An enzyme that catalyzes the conversion of ATP and thymidine to ADP and thymidine 5'-phosphate. Deoxyuridine can also act as an acceptor and dGTP as a donor. (From Enzyme Nomenclature, 1992) EC 2.7.1.21. Deoxythymidine Kinase,Deoxypyrimidine Kinase,Kinase, Deoxypyrimidine,Kinase, Deoxythymidine,Kinase, Thymidine
D015215 Zidovudine A dideoxynucleoside compound in which the 3'-hydroxy group on the sugar moiety has been replaced by an azido group. This modification prevents the formation of phosphodiester linkages which are needed for the completion of nucleic acid chains. The compound is a potent inhibitor of HIV replication, acting as a chain-terminator of viral DNA during reverse transcription. It improves immunologic function, partially reverses the HIV-induced neurological dysfunction, and improves certain other clinical abnormalities associated with AIDS. Its principal toxic effect is dose-dependent suppression of bone marrow, resulting in anemia and leukopenia. AZT (Antiviral),Azidothymidine,3'-Azido-2',3'-Dideoxythymidine,3'-Azido-3'-deoxythymidine,AZT Antiviral,AZT, Antiviral,BW A509U,BWA-509U,Retrovir,3' Azido 2',3' Dideoxythymidine,3' Azido 3' deoxythymidine,Antiviral AZT,BWA 509U,BWA509U
D051381 Rats The common name for the genus Rattus. Rattus,Rats, Laboratory,Rats, Norway,Rattus norvegicus,Laboratory Rat,Laboratory Rats,Norway Rat,Norway Rats,Rat,Rat, Laboratory,Rat, Norway,norvegicus, Rattus
D018259 Herpesvirus 1, Human The type species of SIMPLEXVIRUS causing most forms of non-genital herpes simplex in humans. Primary infection occurs mainly in infants and young children and then the virus becomes latent in the dorsal root ganglion. It then is periodically reactivated throughout life causing mostly benign conditions. HSV-1,Herpes Simplex Virus 1,HHV-1,Herpes Simplex Virus Type 1,Herpesvirus 1 (alpha), Human,Human Herpesvirus 1

Related Publications

F Mao, and T M Rechtin, and R Jones, and A A Cantu, and L S Anderson, and A Radominska, and M P Moyer, and R R Drake
July 1976, Journal of medicinal chemistry,
F Mao, and T M Rechtin, and R Jones, and A A Cantu, and L S Anderson, and A Radominska, and M P Moyer, and R R Drake
March 1989, Biochemical pharmacology,
F Mao, and T M Rechtin, and R Jones, and A A Cantu, and L S Anderson, and A Radominska, and M P Moyer, and R R Drake
April 1991, Journal of medicinal chemistry,
F Mao, and T M Rechtin, and R Jones, and A A Cantu, and L S Anderson, and A Radominska, and M P Moyer, and R R Drake
September 2003, Antiviral chemistry & chemotherapy,
F Mao, and T M Rechtin, and R Jones, and A A Cantu, and L S Anderson, and A Radominska, and M P Moyer, and R R Drake
June 1995, Drug metabolism and disposition: the biological fate of chemicals,
F Mao, and T M Rechtin, and R Jones, and A A Cantu, and L S Anderson, and A Radominska, and M P Moyer, and R R Drake
February 1990, AIDS research and human retroviruses,
F Mao, and T M Rechtin, and R Jones, and A A Cantu, and L S Anderson, and A Radominska, and M P Moyer, and R R Drake
September 1988, Biochemical and biophysical research communications,
F Mao, and T M Rechtin, and R Jones, and A A Cantu, and L S Anderson, and A Radominska, and M P Moyer, and R R Drake
August 1997, Antiviral research,
F Mao, and T M Rechtin, and R Jones, and A A Cantu, and L S Anderson, and A Radominska, and M P Moyer, and R R Drake
August 1976, The Journal of biological chemistry,
F Mao, and T M Rechtin, and R Jones, and A A Cantu, and L S Anderson, and A Radominska, and M P Moyer, and R R Drake
December 1990, Molecular pharmacology,
Copied contents to your clipboard!