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

Authors: Moquin SA, Simon O, Karuna R, Lakshminarayana SB, Yokokawa F, Wang F, Saravanan C, Zhang J, Day CW, Chan K, Wang QY, Lu S, Dong H, Wan KF, Lim SP, Liu W, Seh CC, Chen YL, Xu H, Barkan DT, Kounde CS, Sim WLS, Wang G, Yeo HQ, Zou B, Chan WL, Ding M, Song JG, Li M, Osborne C, Blasco F, Sarko C, Beer D, Bonamy GMC, Sasseville VG, Shi PY, Diagana TT, Yeung BKS, Gu F
Publication: Sci Transl Med
Keywords: fih, FIHSimulator, first-in-human predictions, gastroplus, IVIVE, pbbm, PBPK modeling, physiologically based biopharmaceutics, physiologically based pharmacokinetics
Software: GastroPlus®

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.

By Stephanie A. Moquin, Oliver Simon, Ratna Karuna, Suresh B. Lakshminarayana, Fumiaki Yokokawa, Feng Wang, Chandra Saravanan, Jin Zhang, Craig W., 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. Barkan, Cyrille 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