Enhancement of the anti-HIV-1 activity of ddAdo by coformycin, EHNA and deaza-EHNA derivatives.
2',3'-dideoxyadenosine (ddAdo) and 2',3'-dideoxyinosine (ddIno) are potent and selective inhibitors of the replication of the human immunodeficiency virus type 1 (HIV1) in several cell culture systems. Equipotent in terms of antiviral activity, both compounds selectively inhibit the reverse transcription of HIV-1 by virtue of their conversion into ddATP. In human lymphoid cells ddAdo is converted to the active metabolite, ddATP, but it also undergoes rapid deamination, via adenosine deaminase, to form ddIno. ddIno, like ddAdo, gives rise to dideoxynucleotides of the dideoxy-adenylate series (ddAMP, ddADP and ddATP), as well as to IMP and to adenylate ribonucleotides. With the main object of blocking the deamination of ddAdo, we studied its anti-HIV-1 activity in the presence of different adenosine deaminase inhibitors, namely Coformycin (CF), 9-(erythro-2-hydroxy-3-nonyl) adenine (EHNA) and some deaza-EHNA derivatives. In contrast with reports on 2'-deoxycoformycin (Cooney et al., 1987), the adenosine deaminase inhibitors tested by us showed a significant increase in the antiviral activity of ddAdo, but not of ddIno. Enhancement was obtained with EHNA and CF concentrations up to 250 and > 12,500 times lower than their respective maximum non toxic doses. In combination with EHNA or CF, ddAdo could be used at concentrations up to ten times lower than those required to obtain the same degree of inhibition when ddAdo (or ddIno) was used alone. The use of EHNA or CF in combination with ddAdo at concentrations that inhibit the multiplication of HIV-1, allowed uninfected cells to maintain their normal multiplication rates. In fact, in combination experiments, cytotoxic effects were evident only with doses of EHNA, or CF and ddAdo 10 to 100 or more times higher than those required to inhibit HIV-1 significantly. The in vivo implications of these results for anti-HIV chemotherapy are discussed.
Marongiu
M E
ME
Dipartimento di Biologia Sperimentale, Università di Cagliari, Italy.
Pani
A
A
Tinti
E
E
Grifantini
M
M
Franchetti
P
P
Cristalli
G
G
La Colla
P
P
D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D058892:Adenosine Deaminase Inhibitors; D000998:Antiviral Agents / Q000008:administration & dosage*; D002460:Cell Line; D003070:Coformycin / Q000008:administration & dosage*; D016048:Dideoxyadenosine / Q000008:administration & dosage*; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D014779:Virus Replication / Q000187:drug effects
D058892:Adenosine Deaminase Inhibitors; D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D003070:Coformycin; D016048:Dideoxyadenosine; C010192:9-(2-hydroxy-3-nonyl)adenine; D000225:Adenine