Ten years of dengue drug discovery

Progress and prospects

Siew Pheng Lim, Qing Yin Wang, Christian G. Noble, Yen Liang Chen, Hongping Dong, Bin Zou, Fumiaki Yokokawa, Shahul Nilar, Paul Smith, David Beer, Julien Lescar, Pei-Yong Shi

Research output: Contribution to journalReview article

197 Citations (Scopus)

Abstract

To combat neglected diseases, the Novartis Institute of Tropical Diseases (NITD) was founded in 2002 through private-public funding from Novartis and the 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 rational 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 their poor selectivity, physiochemical or pharmacokinetic properties. Only a few compounds showed efficacy in the AG129 DENV 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 knowledge accumulated during the past decade has provided a better rationale for ongoing dengue drug discovery. Though challenging, we are optimistic that this continuous, concerted effort will lead to an effective dengue therapy.

Original languageEnglish (US)
Pages (from-to)500-519
Number of pages20
JournalAntiviral Research
Volume100
Issue number2
DOIs
StatePublished - 2013
Externally publishedYes

Fingerprint

Dengue Virus
Dengue
Drug Discovery
balapiravir
Antiviral Agents
Neglected Diseases
Economic Development
Singapore
Enzyme Assays
Viral Proteins
Virus Replication
Culicidae
Nucleosides
Hepacivirus
Computer Simulation
Vaccines
Pharmacokinetics
Clinical Trials
Safety

Keywords

  • Antiviral
  • Dengue virus
  • Drug discovery
  • Flavivirus

ASJC Scopus subject areas

  • Virology
  • Pharmacology

Cite this

Lim, S. P., Wang, Q. Y., Noble, C. G., Chen, Y. L., Dong, H., Zou, B., ... Shi, P-Y. (2013). Ten years of dengue drug discovery: Progress and prospects. Antiviral Research, 100(2), 500-519. https://doi.org/10.1016/j.antiviral.2013.09.013

Ten years of dengue drug discovery : Progress and prospects. / Lim, Siew Pheng; Wang, Qing Yin; Noble, Christian G.; Chen, Yen Liang; Dong, Hongping; Zou, Bin; Yokokawa, Fumiaki; Nilar, Shahul; Smith, Paul; Beer, David; Lescar, Julien; Shi, Pei-Yong.

In: Antiviral Research, Vol. 100, No. 2, 2013, p. 500-519.

Research output: Contribution to journalReview article

Lim, SP, Wang, QY, Noble, CG, Chen, YL, Dong, H, Zou, B, Yokokawa, F, Nilar, S, Smith, P, Beer, D, Lescar, J & Shi, P-Y 2013, 'Ten years of dengue drug discovery: Progress and prospects', Antiviral Research, vol. 100, no. 2, pp. 500-519. https://doi.org/10.1016/j.antiviral.2013.09.013
Lim SP, Wang QY, Noble CG, Chen YL, Dong H, Zou B et al. Ten years of dengue drug discovery: Progress and prospects. Antiviral Research. 2013;100(2):500-519. https://doi.org/10.1016/j.antiviral.2013.09.013
Lim, Siew Pheng ; Wang, Qing Yin ; Noble, Christian G. ; Chen, Yen Liang ; Dong, Hongping ; Zou, Bin ; Yokokawa, Fumiaki ; Nilar, Shahul ; Smith, Paul ; Beer, David ; Lescar, Julien ; Shi, Pei-Yong. / Ten years of dengue drug discovery : Progress and prospects. In: Antiviral Research. 2013 ; Vol. 100, No. 2. pp. 500-519.
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