Activity against human immunodeficiency virus type 1, intracellular metabolism, and effects on human DNA polymerases of 4'-ethynyl-2-fluoro-2'-deoxyadenosine. 2007

Hirotomo Nakata, and Masayuki Amano, and Yasuhiro Koh, and Eiichi Kodama, and Guangwei Yang, and Christopher M Bailey, and Satoru Kohgo, and Hiroyuki Hayakawa, and Masao Matsuoka, and Karen S Anderson, and Yung-Chi Cheng, and Hiroaki Mitsuya
Department of Infectious, Kumamoto University School of Medicine, 1-1-1 Honjo, Kumamoto, Japan.

We examined the intracytoplasmic anabolism and kinetics of antiviral activity against human immunodeficiency virus type 1 (HIV-1) of a nucleoside reverse transcriptase inhibitor, 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA), which has potent activity against wild-type and multidrug-resistant HIV-1 strains. When CEM cells were exposed to 0.1 microM [(3)H]EFdA or [(3)H]3'-azido-2',3'-dideoxythymidine (AZT) for 6 h, the intracellular EFdA-triphosphate (TP) level was 91.6 pmol/10(9) cells, while that of AZT was 396.5 pmol/10(9) cells. When CEM cells were exposed to 10 microM [(3)H]EFdA, the amount of EFdA-TP increased by 22-fold (2,090 pmol/10(9) cells), while the amount of [(3)H]AZT-TP increased only moderately by 2.4-fold (970 pmol/10(9) cells). The intracellular half-life values of EFdA-TP and AZT-TP were approximately 17 and approximately 3 h, respectively. When MT-4 cells were cultured with 0.01 microM EFdA for 24 h, thoroughly washed to remove EFdA, further cultured without EFdA for various periods of time, exposed to HIV-1(NL4-3), and cultured for an additional 5 days, the protection values were 75 and 47%, respectively, after 24 and 48 h with no drug incubation, while those with 1 microM AZT were 55 and 9.2%, respectively. The 50% inhibitory concentration values of EFdA-TP against human polymerases alpha, beta, and gamma were >100 microM, >100 microM, and 10 microM, respectively, while those of ddA-TP were >100 microM, 0.2 microM, and 0.2 microM, respectively. These data warrant further development of EFdA as a potential therapeutic agent for those patients who harbor wild-type HIV-1 and/or multidrug-resistant variants.

UI MeSH Term Description Entries
D008826 Microbial Sensitivity Tests Any tests that demonstrate the relative efficacy of different chemotherapeutic agents against specific microorganisms (i.e., bacteria, fungi, viruses). Bacterial Sensitivity Tests,Drug Sensitivity Assay, Microbial,Minimum Inhibitory Concentration,Antibacterial Susceptibility Breakpoint Determination,Antibiogram,Antimicrobial Susceptibility Breakpoint Determination,Bacterial Sensitivity Test,Breakpoint Determination, Antibacterial Susceptibility,Breakpoint Determination, Antimicrobial Susceptibility,Fungal Drug Sensitivity Tests,Fungus Drug Sensitivity Tests,Sensitivity Test, Bacterial,Sensitivity Tests, Bacterial,Test, Bacterial Sensitivity,Tests, Bacterial Sensitivity,Viral Drug Sensitivity Tests,Virus Drug Sensitivity Tests,Antibiograms,Concentration, Minimum Inhibitory,Concentrations, Minimum Inhibitory,Inhibitory Concentration, Minimum,Inhibitory Concentrations, Minimum,Microbial Sensitivity Test,Minimum Inhibitory Concentrations,Sensitivity Test, Microbial,Sensitivity Tests, Microbial,Test, Microbial Sensitivity,Tests, Microbial Sensitivity
D002478 Cells, Cultured Cells propagated in vitro in special media conducive to their growth. Cultured cells are used to study developmental, morphologic, metabolic, physiologic, and genetic processes, among others. Cultured Cells,Cell, Cultured,Cultured Cell
D003470 Culture Media Any liquid or solid preparation made specifically for the growth, storage, or transport of microorganisms or other types of cells. The variety of media that exist allow for the culturing of specific microorganisms and cell types, such as differential media, selective media, test media, and defined media. Solid media consist of liquid media that have been solidified with an agent such as AGAR or GELATIN. Media, Culture
D003839 Deoxyadenosines Adenosine molecules which can be substituted in any position, but are lacking one hydroxyl group in the ribose part of the molecule. Adenine Deoxyribonucleosides,Adenylyldeoxyribonucleosides,Deoxyadenosine Derivatives,Deoxyribonucleosides, Adenine,Derivatives, Deoxyadenosine
D004259 DNA-Directed DNA Polymerase DNA-dependent DNA polymerases found in bacteria, animal and plant cells. During the replication process, these enzymes catalyze the addition of deoxyribonucleotide residues to the end of a DNA strand in the presence of DNA as template-primer. They also possess exonuclease activity and therefore function in DNA repair. DNA Polymerase,DNA Polymerases,DNA-Dependent DNA Polymerases,DNA Polymerase N3,DNA Dependent DNA Polymerases,DNA Directed DNA Polymerase,DNA Polymerase, DNA-Directed,DNA Polymerases, DNA-Dependent,Polymerase N3, DNA,Polymerase, DNA,Polymerase, DNA-Directed DNA,Polymerases, DNA,Polymerases, DNA-Dependent DNA
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D014316 Tritium The radioactive isotope of hydrogen also known as hydrogen-3. It contains two NEUTRONS and one PROTON in its nucleus and decays to produce low energy BETA PARTICLES. Hydrogen-3,Hydrogen 3
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
D015496 CD4-Positive T-Lymphocytes A critical subpopulation of T-lymphocytes involved in the induction of most immunological functions. The HIV virus has selective tropism for the T4 cell which expresses the CD4 phenotypic marker, a receptor for HIV. In fact, the key element in the profound immunosuppression seen in HIV infection is the depletion of this subset of T-lymphocytes. T4 Cells,T4 Lymphocytes,CD4-Positive Lymphocytes,CD4 Positive T Lymphocytes,CD4-Positive Lymphocyte,CD4-Positive T-Lymphocyte,Lymphocyte, CD4-Positive,Lymphocytes, CD4-Positive,T-Lymphocyte, CD4-Positive,T-Lymphocytes, CD4-Positive,T4 Cell,T4 Lymphocyte
D015497 HIV-1 The type species of LENTIVIRUS and the etiologic agent of AIDS. It is characterized by its cytopathic effect and affinity for the T4-lymphocyte. Human immunodeficiency virus 1,HIV-I,Human Immunodeficiency Virus Type 1,Immunodeficiency Virus Type 1, Human

Related Publications

Hirotomo Nakata, and Masayuki Amano, and Yasuhiro Koh, and Eiichi Kodama, and Guangwei Yang, and Christopher M Bailey, and Satoru Kohgo, and Hiroyuki Hayakawa, and Masao Matsuoka, and Karen S Anderson, and Yung-Chi Cheng, and Hiroaki Mitsuya
November 2021, Antimicrobial agents and chemotherapy,
Hirotomo Nakata, and Masayuki Amano, and Yasuhiro Koh, and Eiichi Kodama, and Guangwei Yang, and Christopher M Bailey, and Satoru Kohgo, and Hiroyuki Hayakawa, and Masao Matsuoka, and Karen S Anderson, and Yung-Chi Cheng, and Hiroaki Mitsuya
December 2013, Antimicrobial agents and chemotherapy,
Hirotomo Nakata, and Masayuki Amano, and Yasuhiro Koh, and Eiichi Kodama, and Guangwei Yang, and Christopher M Bailey, and Satoru Kohgo, and Hiroyuki Hayakawa, and Masao Matsuoka, and Karen S Anderson, and Yung-Chi Cheng, and Hiroaki Mitsuya
January 2008, The international journal of biochemistry & cell biology,
Hirotomo Nakata, and Masayuki Amano, and Yasuhiro Koh, and Eiichi Kodama, and Guangwei Yang, and Christopher M Bailey, and Satoru Kohgo, and Hiroyuki Hayakawa, and Masao Matsuoka, and Karen S Anderson, and Yung-Chi Cheng, and Hiroaki Mitsuya
September 2009, Antimicrobial agents and chemotherapy,
Hirotomo Nakata, and Masayuki Amano, and Yasuhiro Koh, and Eiichi Kodama, and Guangwei Yang, and Christopher M Bailey, and Satoru Kohgo, and Hiroyuki Hayakawa, and Masao Matsuoka, and Karen S Anderson, and Yung-Chi Cheng, and Hiroaki Mitsuya
August 2014, The Journal of biological chemistry,
Hirotomo Nakata, and Masayuki Amano, and Yasuhiro Koh, and Eiichi Kodama, and Guangwei Yang, and Christopher M Bailey, and Satoru Kohgo, and Hiroyuki Hayakawa, and Masao Matsuoka, and Karen S Anderson, and Yung-Chi Cheng, and Hiroaki Mitsuya
August 1999, Antimicrobial agents and chemotherapy,
Hirotomo Nakata, and Masayuki Amano, and Yasuhiro Koh, and Eiichi Kodama, and Guangwei Yang, and Christopher M Bailey, and Satoru Kohgo, and Hiroyuki Hayakawa, and Masao Matsuoka, and Karen S Anderson, and Yung-Chi Cheng, and Hiroaki Mitsuya
February 2017, Organic letters,
Hirotomo Nakata, and Masayuki Amano, and Yasuhiro Koh, and Eiichi Kodama, and Guangwei Yang, and Christopher M Bailey, and Satoru Kohgo, and Hiroyuki Hayakawa, and Masao Matsuoka, and Karen S Anderson, and Yung-Chi Cheng, and Hiroaki Mitsuya
July 2018, Current opinion in HIV and AIDS,
Hirotomo Nakata, and Masayuki Amano, and Yasuhiro Koh, and Eiichi Kodama, and Guangwei Yang, and Christopher M Bailey, and Satoru Kohgo, and Hiroyuki Hayakawa, and Masao Matsuoka, and Karen S Anderson, and Yung-Chi Cheng, and Hiroaki Mitsuya
September 2012, Antimicrobial agents and chemotherapy,
Hirotomo Nakata, and Masayuki Amano, and Yasuhiro Koh, and Eiichi Kodama, and Guangwei Yang, and Christopher M Bailey, and Satoru Kohgo, and Hiroyuki Hayakawa, and Masao Matsuoka, and Karen S Anderson, and Yung-Chi Cheng, and Hiroaki Mitsuya
August 2017, Antimicrobial agents and chemotherapy,
Copied contents to your clipboard!