ReviewThe search for nucleoside/nucleotide analog inhibitors of dengue virus

- Nucleos(t)ide inhibitors are the most attractive class of anti-dengue drug.
- The RdRp of dengue virus is the most attractive target due to proven track record.
- Most recent nucleos(t)ide drugs are monophosphate prodrugs with better potency.
- Unpredictable toxicities remain one of the main reasons for clinical failure.
- Combination therapies could minimize resistance and improve therapeutic index.

Nucleoside analogs represent the largest class of antiviral agents and have been actively pursued for potential therapy of dengue virus (DENV) infection. Early success in the treatment of human immunodeficiency virus (HIV) infection and the recent approval of sofosbuvir for chronic hepatitis C have provided proof of concept for this class of compounds in clinics. Here we review (i) nucleoside analogs with known anti-DENV activity; (ii) challenges of the nucleoside antiviral approach for dengue; and (iii) potential strategies to overcome these challenges. This article forms part of a symposium in Antiviral Research on flavivirus drug discovery.