Metabolism and anti-human immunodeficiency virus-1 activity of 2-halo-2',3'-dideoxyadenosine derivatives.
Both 2',3'-dideoxyadenosine and 2',3'-dideoxyinosine have been shown (Mitsuya, H., and Broder, S. (1987) Nature 325, 773-778) to have in vitro activity against the human immunodeficiency virus-1 (HIV). However, these dideoxynucleosides may be catabolized by human T cells, even when adenosine deaminase is inhibited by deoxycoformycin. To overcome this problem, we have synthesized the 2-fluoro-, 2-chloro-, and 2-bromo-derivatives of 2',3'-dideoxyadenosine. The metabolism and anti-HIV activity of the 2-halo-2',3'-dideoxyadenosine derivatives and of 2',3'-dideoxyadenosine were compared. The 2-halo-2',3'-dideoxyadenosine derivatives were not deaminated significantly by cultured CEM T lymphoblasts. Experiments with 2-chloro-2',3'-dideoxyadenosine showed that the T cells converted the dideoxynucleoside to the 5'-monophosphate, 5'-diphosphate, and 5'-triphosphate metabolites. At concentrations lower than those producing cytotoxicity in uninfected cells (3-10 microM), the 2-halo-2',3-dideoxyadenosine derivatives inhibited the cytopathic effects of HIV toward MT-2 T lymphoblasts, and retarded viral replication in CEM T lymphoblasts. Experiments with a deoxycytidine kinase-deficient mutant CEM T cell line showed that this enzyme was necessary for the phosphorylation and anti-HIV activity of the 2-chloro-2',3'-dideoxyadenosine. In contrast, 2',3'-dideoxyadenosine was phosphorylated by the deoxycytidine kinase-deficient mutant and retained anti-HIV activity in this cell line. Thus, the 2-halo derivatives of 2',3'-dideoxyadenosine, in contrast to 2',3'-dideoxyadenosine itself, are not catabolized by T cells. Their anti-HIV and anti-proliferative activities are manifest only in cells expressing deoxycytidine kinase. The in vivo implications of these results for anti-HIV chemotherapy are discussed.
Haertle
T
T
Department of Basic and Clinical Research, Research Institute of Scripps Clinic, La Jolla, California 92037.
Carrera
C J
CJ
Wasson
D B
DB
Sowers
L C
LC
Richman
D D
DD
Carson
D A
DA
D000659:AMP Deaminase / Q000037:antagonists & inhibitors; D058892:Adenosine Deaminase Inhibitors; D002460:Cell Line; D003070:Coformycin / Q000494:pharmacology; D003839:Deoxyadenosines / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D003842:Deoxycytidine Kinase / Q000378:metabolism; D016048:Dideoxyadenosine / Q000031:analogs & derivatives; D015224:Dideoxynucleosides; D006678:HIV / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D010766:Phosphorylation; D013601:T-Lymphocytes / Q000378:metabolism*; D014779:Virus Replication / Q000187:drug effects
D058892:Adenosine Deaminase Inhibitors; D003839:Deoxyadenosines; D015224:Dideoxynucleosides; D003070:Coformycin; C055503:2-bromo-2',3'-dideoxyadenosine; C055504:2-chloro-2',3'-dideoxyadenosine; C055502:2-fluoro-2',3'-dideoxyadenosine; D016048:Dideoxyadenosine; D003842:Deoxycytidine Kinase; D000659:AMP Deaminase