Peptides as Therapeutic Agents for Dengue Virus

Chew, Miaw-Fang; Poh, Keat-Seong; Poh, Chit-Laa

The lack of efficient vector control strategies and the uncertainty of long-term protective efficacy of CYD-TDV vaccine against all four DENV serotypes call for an urgent need for dengue therapeutics, especially in endemic countries with poor resource setting. There are no antiviral drugs available and at present, supportive treatment with emphasis on fluid therapy and close clinical monitoring during the critical phase of illness are the only course of action for dengue disease. Many antiviral candidates have failed to reach clinical trials due to their poor selectivity and physiochemical or pharmacokinetic properties [20] . Although nucleoside analogs, such as NITD-008 and balapiravir, have entered preclinical animal safety study and clinical trials, they were terminated due to lack of potency [21] . Balapiravir, for instance, did not improve the clinical and virological parameters in patients in the phase II clinical trial, although it was shown to have good in vitro antiviral activities with EC50 values of 1.3-3.2 µM in DENV infection assays using primary human macrophages [21] . Treatment of DENV-infected mice with another nucleoside analog NITD-008, on the other hand, completely prevented mice death, but severe adverse events were observed in rats and dogs after two weeks of oral dosing [20, 22] . Likewise, other anti-DENV candidates, including chloroquine, prednisolone, celgosivir and lovastatin, have gone through clinical trials but failed to meet the defined primary end points, whereby neither significant viremia nor evidence of beneficial effects on clinical manifestations was observed [23] [24] [25] [26] . At present, two candidates, namely ivermectin and ketotifen, are undergoing clinical trials (trial number NCT02045069 and NCT02673840, respectively). However, their long-term clinical efficacies remain to be determined. In contrast to small molecules, peptides are generally known to have high selectivity and possess relatively safe characteristics which make them attractive pharmacological candidates [27] . Due to their attractive pharmacological profiles, this review will highlight the current status and the rational drug design of antiviral peptides and peptidomimetics as therapeutics for dengue.