1. NITD-688, a pan-serotype inhibitor of the dengue virus NS4B protein, shows favorable pharmacokinetics and efficacy in preclinical animal models
- Author
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Haoying Xu, Wei Lin Sandra Sim, Cheah Chen Seh, Feng Wang, Thierry T. Diagana, Wai Ling Chan, Jae-Geun Song, Kah Fei Wan, Bin Zou, Ghislain M. C. Bonamy, David Beer, David T. Barkan, Min Li, Stephanie A. Moquin, Francesca Blasco, Suresh B. Lakshminarayana, Jin Zhang, Oliver Simon, Vito G. Sasseville, Craig W. Day, Qing-Yin Wang, Chandrassegar Saravanan, Katherine Chan, Fumiaki Yokokawa, Bryan K. S. Yeung, Ratna Karuna, Hui-Quan Yeo, Colin Osborne, Christopher Sarko, Pei Yong Shi, Hongping Dong, Mei Ding, Siew Pheng Lim, Yen Liang Chen, Feng Gu, Cyrille Kounde, Gang Wang, Siyan Lu, and Wei Liu
- Subjects
0301 basic medicine ,biology ,medicine.drug_class ,business.industry ,030106 microbiology ,Viremia ,General Medicine ,Dengue virus ,Pharmacology ,medicine.disease_cause ,medicine.disease ,biology.organism_classification ,Dengue fever ,Bioavailability ,03 medical and health sciences ,Flavivirus ,030104 developmental biology ,Pharmacokinetics ,medicine ,Potency ,Antiviral drug ,business - 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.
- Published
- 2021