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

Stephanie A. Moquin, Oliver Simon, Ratna Karuna, Suresh B. Lakshminarayana, Fumiaki Yokokawa, Feng Wang, Chandra Saravanan, Jin Zhang, Craig W. Day, Katherine Chan, Qing Yin Wang, Siyan Lu, Hongping Dong, Kah Fei Wan, Siew Pheng Lim, Wei Liu, Cheah Chen Seh, Yen Liang Chen, Haoying Xu, David T. BarkanCyrille S. Kounde, Wei Lin Sandra Sim, Gang Wang, Hui Quan Yeo, Bin Zou, Wai Ling Chan, Mei Ding, Jae Geun Song, Min Li, Colin Osborne, Francesca Blasco, Christopher Sarko, David Beer, Ghislain M.C. Bonamy, Vito G. Sasseville, Pei Yong Shi, Thierry T. Diagana, Bryan K.S. Yeung, Feng Gu

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish (US)
Article numbereabb2181
JournalScience Translational Medicine
Volume13
Issue number579
DOIs
StatePublished - Feb 3 2021
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)

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