The antifungal activity of the nucleoside analog 3*-deoxyadenosine (cordycepin) was studied in a murine model of invasive candidiasis. When protected from deamination by either deoxycoformycin or coformycin, both of which are adenosine deaminase inhibitors, cordycepin exhibited potent antifungal efficacy, as demonstrated by prolongation of survival and a decrease in CFU in the kidneys of mice treated with cordycepin plus an adenosine deaminase inhibitor. The antifungal effect was seen with three different Candida isolates: Candida albicans 64, a relatively fluconazole-resistant clinical isolate of C. albicans (MIC, 16 mg/ml), and the fluconazole-resistant Candida krusei. Cordycepin and related compounds may provide another avenue for the discovery of clinically useful antifungal drugs. It has recently been shown that the nucleoside analog 39deoxyadenosine (also known as cordycepin), when protected against conversion to 39-deoxyinosine by the enzyme adenosine deaminase (ADA), exhibits specific cytotoxic activity against leukemia cells expressing terminal deoxynucleotidyl transferase (1). Over 20 years ago, this nucleoside was studied as a potential antiparasitic agent and found to markedly inhibit the in vitro proliferation of Plasmodium species (8). However, in follow-up in vivo therapeutic studies in murine disease models, the need to protect cordycepin from deamination by ADA (thus preventing the formation of the cytotoxically inactive derivative 39-deoxyinosine) was not appreciated, and because the in vitro antiproliferative activity was not seen in vivo, cordycepin was not advanced into clinical trials for treatment of parasitic disease. We have recently found that when cordycepin is protected from ADA deamination (by either coformycin or deoxycoformycin, both of which are ADA inhibitors), the potent in vitro antimalarial activity of cordycepin is retained in vivo (9).
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