Abstract P06: Anticancer agent 3-deazauridine has the potential to be effective against COVID-19 due to its inhibition of replication of RNA viruses

2021 
3-Deazauridine (3DU) is a nucleoside analogue that was investigated for its antineoplastic activity in cancer patients. 3DU after its phosphorylation in cells to its 5’-triphosphate is a potent inhibitor of CTP synthetase. Inhibition of this enzyme results in a reduction in cellular CTP and inhibition of RNA synthesis. This action of 3DU can also inhibit RNA synthesis since the viral RNA polymerase requires CTP for replication of RNA. 3DU was reported to inhibit the in vitro replication of the RNA influenza virus at concentrations in the range of 40 µM (1) and should also have the potential to inhibit the replication of SARS-CoV-2. In a pilot clinical study, we treated a patient with acute lymphoid leukemia with 3DU at doses ranging from 120 to 360 mg/kg using a continuous intravenous infusion ranging from 40 to 72 hr. (2). The objective of the study was to determine if 3DU could enhance the antileukemic action of the inhibitor of DNA methylation, decitabine, and overcome the problem of drug resistance to this deoxycytidine analogue. Partial responses were observed indicating that pharmacological action of 3DU could accomplish this objective. There were minimal signs of toxicity in this clinical study on 3DU which exhibited plasma concentrations of this analogue in the range that inhibit RNA virus replication. This observation suggests that it would be safe to use 3DU in patients with COVID-19. 3DU has a rapid onset of action with a significant sign of antineoplastic action observable after a 4 h in vitro treatment of human leukemic cells. This pharmacological property rapid action of 3DU may be very important in patients with advanced COVID-19 to inhibit the virus is during its rapid replication phase and prevent progression of the disease to acute lung inflammation. It would be interesting to test this hypothesis in advanced COVID-19 patients at high risk for disease progression. For an initial pilot study I recommend a 36 h infusion of 3DU at a total dose of 120 mg/kg. It is possible that therapy with 3DU may have the potential to rescue patients with advance COVID-19. References 1. Shannon, W.M., Arnett, G., Schabel, F.M., Jr., 1972. 3-Deazauridine: inhibition of ribonucleic acid virus-induced cytopathogenic effects in vitro. Antimicrob. Agents Chemother. 2, 159–163. 2. Raynal, N.J., Momparler, L.F., Rivard, G.E., Momparler, R.L., 2011. 3-Deazauridine enhances the antileukemic action of 5-aza-29-deoxycytidine and targets drug-resistance due to deficiency in deoxycytidine kinase. Leuk. Res. 35, 10-118. Citation Format: Richard Momparler. Anticancer agent 3-deazauridine has the potential to be effective against COVID-19 due to its inhibition of replication of RNA viruses [abstract]. In: Proceedings of the AACR Virtual Meeting: COVID-19 and Cancer; 2021 Feb 3-5. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(6_Suppl):Abstract nr P06.
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