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Ten years of dengue drug discovery: progress and prospects.

Lim, Siew Pheng and Wang, Qingyin and Noble, Christian Guy and Chen, Yen Liang and Dong, Hongping and Zou, Bin and Yokokawa, Fumiaki and Nilar, Shahul Hameed and Smith, Paul William and Beer, David John and julien, lescar and Shi, Pei-Yong (2013) Ten years of dengue drug discovery: progress and prospects. Anti-viral Research Journal.

Abstract

To combat neglected diseases, Novartis Institute of Tropical Diseases (NITD) was founded in 2002 through private-public fund from Novartis and Singapore Economic Development Board. One of NITD’s missions is to develop antivirals for dengue virus (DENV), the most prevalent mosquito-borne viral pathogen. Neither vaccine nor antiviral is currently available for DENV. Here we review the progress in dengue drug discovery made at NITD as well as the major discoveries made by academia and other companies. Four strategies have been pursued to identify inhibitors of DENV through targeting both viral and host proteins. (i) HTS (high-throughput screening) using virus replication assays; (ii) HTS using viral enzyme assays; (iii) Structure-based in silico docking and rationale design; (iv) Repurposing hepatitis C virus inhibitors for DENV. Along the developmental process from hit finding to clinical candidate, many inhibitors did not advance beyond the stage of hit-to-lead optimization, due to poor selectivity, physiochemical properties, or pharmacokinetic properties. Only a few compounds showed efficacy in the AG129 mouse model. Two nucleoside analogs, NITD-008 and Balapiravir, entered preclinical animal safety study and clinic trial, but both were terminated due to toxicity and lack of potency, respectively. Celgosivir, a host alpha-glucosidase inhibitor, is currently under clinical trial; its clinical efficacy remains to be determined. The experience accumulated during the past decade has provided better rationale for the ongoing dengue drug discovery. Though challenging, we are optimistic that the continuous, concerted effort will lead to an effective dengue therapy.

Item Type: Article
Additional Information: Review
Keywords: Drug discovery; antiviral; dengue virus; flavivirus
Date Deposited: 13 Oct 2015 13:13
Last Modified: 13 Oct 2015 13:13
URI: https://oak.novartis.com/id/eprint/10543

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