학술논문
NITD-688, a pan-serotype inhibitor of the dengue virus NS4B protein, shows favorable pharmacokinetics and efficacy in preclinical animal models.
Document Type
Academic Journal
Author
Moquin SA; Novartis Institutes for Biomedical Research, Emeryville, CA 94608, USA.; Novartis Institute for Tropical Diseases, Emeryville, CA 94608, USA.; Simon O; Novartis (Singapore) Pte Ltd, Singapore 117432, Singapore.; Karuna R; Novartis Institute for Tropical Diseases, Singapore 138670, Singapore.; Lakshminarayana SB; Novartis Institute for Tropical Diseases, Emeryville, CA 94608, USA.; Yokokawa F; Novartis Institute for Tropical Diseases, Emeryville, CA 94608, USA.; Wang F; Novartis Institutes for Biomedical Research, Emeryville, CA 94608, USA.; Saravanan C; Novartis Institutes for Biomedical Research, Translational Medicine: Preclinical Safety, Cambridge, MA 02139, USA.; Zhang J; Novartis Institutes for Biomedical Research, Translational Medicine: Pharmacokinetics, East Hanover, NJ 07936, USA.; Day CW; Institute for Antiviral Research, Utah State University, Logan, UT 84322, USA.; Chan K; Novartis Institute for Tropical Diseases, Emeryville, CA 94608, USA.; Wang QY; Novartis Institute for Tropical Diseases, Singapore 138670, Singapore.; Lu S; Novartis Institute for Tropical Diseases, Singapore 138670, Singapore.; Dong H; Novartis Institute for Tropical Diseases, Singapore 138670, Singapore.; Wan KF; Novartis Institute for Tropical Diseases, Singapore 138670, Singapore.; Lim SP; Novartis Institute for Tropical Diseases, Singapore 138670, Singapore.; Liu W; Novartis Institute for Tropical Diseases, Singapore 138670, Singapore.; Seh CC; Novartis Institute for Tropical Diseases, Singapore 138670, Singapore.; Chen YL; Novartis Institute for Tropical Diseases, Emeryville, CA 94608, USA.; Xu H; Novartis Institute for Tropical Diseases, Singapore 138670, Singapore.; Barkan DT; Novartis Institutes for Biomedical Research, Emeryville, CA 94608, USA.; Kounde CS; Novartis Institute for Tropical Diseases, Singapore 138670, Singapore.; Sim WLS; Novartis Institute for Tropical Diseases, Singapore 138670, Singapore.; Wang G; Novartis Institute for Tropical Diseases, Singapore 138670, Singapore.; Yeo HQ; Novartis Institute for Tropical Diseases, Singapore 138670, Singapore.; Zou B; Novartis Institute for Tropical Diseases, Singapore 138670, Singapore.; Chan WL; Novartis Institute for Tropical Diseases, Singapore 138670, Singapore.; Ding M; Novartis Institute for Tropical Diseases, Singapore 138670, Singapore.; Song JG; Novartis Institutes for Biomedical Research, Emeryville, CA 94608, USA.; Li M; Novartis Institutes for Biomedical Research, Emeryville, CA 94608, USA.; Osborne C; Novartis Institute for Tropical Diseases, Emeryville, CA 94608, USA.; Blasco F; Novartis Institute for Tropical Diseases, Singapore 138670, Singapore.; Sarko C; Novartis Institute for Tropical Diseases, Emeryville, CA 94608, USA.; Beer D; Novartis Institute for Tropical Diseases, Singapore 138670, Singapore.; Bonamy GMC; Novartis Institute for Tropical Diseases, Singapore 138670, Singapore.; Sasseville VG; Novartis Institutes for Biomedical Research, Translational Medicine: Preclinical Safety, Cambridge, MA 02139, USA.; Shi PY; Novartis Institute for Tropical Diseases, Singapore 138670, Singapore.; Diagana TT; Novartis Institute for Tropical Diseases, Emeryville, CA 94608, USA.; Yeung BKS; Novartis Institute for Tropical Diseases, Singapore 138670, Singapore. bryan.yeung@rightfund.org feng.gu@novartis.com.; Gu F; Novartis Institute for Tropical Diseases, Emeryville, CA 94608, USA. bryan.yeung@rightfund.org feng.gu@novartis.com.
Source
Publisher: American Association for the Advancement of Science Country of Publication: United States NLM ID: 101505086 Publication Model: Print Cited Medium: Internet ISSN: 1946-6242 (Electronic) Linking ISSN: 19466234 NLM ISO Abbreviation: Sci Transl Med Subsets: MEDLINE
Subject
Language
English
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.
(Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
(Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)