Research ArticleDengue

NITD-688, a pan-serotype inhibitor of the dengue virus NS4B protein, shows favorable pharmacokinetics and efficacy in preclinical animal models

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Science Translational Medicine  03 Feb 2021:
Vol. 13, Issue 579, eabb2181
DOI: 10.1126/scitranslmed.abb2181

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A versatile antiviral

Dengue virus (DENV) is a mosquito-borne flavivirus that lacks any effective antiviral treatments. There are four serotypes of DENV, all of which can cause disease, including dengue fever, dengue shock syndrome, or dengue hemorrhagic fever. Thus, an antiviral drug needs to be effective against all four serotypes. Here, Moquin et al. identify an inhibitor of the DENV protein NS4B that is effective against all four serotypes in vitro and against DENV-2 in vivo in mice. The authors show that the inhibitor, NITD-688, is well tolerated and has favorable pharmacokinetic properties in rats and dogs and decreased viremia in mice when treated up to 2 days after DENV infection. These findings suggest that NITD-688 is a promising candidate for a DENV antiviral drug.

Abstract

Dengue virus (DENV) is a mosquito-borne flavivirus that poses a threat to public health, yet no antiviral drug is available. We performed a high-throughput phenotypic screen using the Novartis compound library and identified candidate chemical inhibitors of DENV. This chemical series was optimized to improve properties such as anti-DENV potency and solubility. The lead compound, NITD-688, showed strong potency against all four serotypes of DENV and demonstrated excellent oral efficacy in infected AG129 mice. There was a 1.44-log reduction in viremia when mice were treated orally at 30 milligrams per kilogram twice daily for 3 days starting at the time of infection. NITD-688 treatment also resulted in a 1.16-log reduction in viremia when mice were treated 48 hours after infection. Selection of resistance mutations and binding studies with recombinant proteins indicated that the nonstructural protein 4B is the target of NITD-688. Pharmacokinetic studies in rats and dogs showed a long elimination half-life and good oral bioavailability. Extensive in vitro safety profiling along with exploratory rat and dog toxicology studies showed that NITD-688 was well tolerated after 7-day repeat dosing, demonstrating that NITD-688 may be a promising preclinical candidate for the treatment of dengue.

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