Ten years of dengue drug discovery: Progress and prospects

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

doi:10.1016/j.antiviral.2013.09.013

Cited by 326 publications

(279 citation statements)

References 174 publications

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“…As reasoned earlier, the current lack of a successful protease inhibitor drug could be because most of the previous attempts have targeted the flavivirus NS3 protease active site [21][22][23][24]. Because the NS2B co-factor binding is essential for the NS3 protease function [13,14,48], inhibitors preventing the NS2B-NS3 interaction could provide a promising alternative approach.…”

Section: Discussionmentioning

confidence: 99%

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Existing drugs as broad-spectrum and potent inhibitors for Zika virus by targeting NS2B-NS3 interaction

et al. 2017

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Recent outbreaks of Zika virus (ZIKV) highlight an urgent need for therapeutics.The protease complex NS2B-NS3 plays essential roles during flaviviral polyprotein processing, and thus represents an attractive drug target. Here, we developed a split luciferase complementation-based high-throughput screening assay to identify orthosteric inhibitors that directly target flavivirus NS2B-NS3 interactions. By screening a total of 2 816 approved and investigational drugs, we identified three potent candidates, temoporfin, niclosamide, and nitazoxanide, as flavivirus NS2B-NS3 interaction inhibitors with nanomolar potencies. Significantly, the most potent compound, temoporfin, not only inhibited ZIKV replication in human placental and neural progenitor cells, but also prevented ZIKV-induced viremia and mortality in mouse models. Structural docking suggests that temoporfin potentially binds NS3 pockets that hold critical NS2B residues, thus inhibiting flaviviral polyprotein processing in a non-competitive manner. As these drugs have already been approved for clinical use in other indications either in the USA or other countries, they represent promising and easily developed therapies for the management of infections by ZIKV and other flaviviruses.

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Section: Discussionmentioning

confidence: 99%

“…Most attempts to develop flavivirus protease inhibitors have focused on the NS3 active site with limited success, possibly due to two of the site's features (reviewed in [21][22][23][24]). First, the active site is flat and featureless, which making it difficult to design specific and potent inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Existing drugs as broad-spectrum and potent inhibitors for Zika virus by targeting NS2B-NS3 interaction

et al. 2017

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“…18 However, the promising in vitro binding affinities come at the expense of pharmacokinetic properties, such as membrane permeability and metabolic stability, which is challenged by the increased polarity through the incorporation of highly basic residues and the peptidic character of the compounds. 19 The first reported small peptidic inhibitors against DENV protease were N-benzoyl-capped di-, tri-, and tetrapeptides linked to C-terminal electrophilic warheads that bind covalently to the catalytic serine. The most active derivatives incorporated trifluoromethyl ketone and boronic acid as electrophiles, and reached nanomolar binding affinities of 850 and 43 nM, respectively.…”

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confidence: 99%

C-Terminal Residue Optimization and Fragment Merging: Discovery of a Potent Peptide-Hybrid Inhibitor of Dengue Protease

Behnam

Nitsche

Vechi

et al. 2014

ACS Med. Chem. Lett.

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Dengue virus protease is a promising target for the development of antiviral drugs. We describe here a two-step rational optimization that led to the discovery of the potent inhibitor 35 with nanomolar binding affinity at dengue protease serotype 2 (IC 50 = 0.6 μM, K i = 0.4 μM). First, a large number of natural and non-natural amino acids were screened at the C-terminal position of the previously reported, canonical peptide sequence (Cap-Arg-Lys-Nle-NH 2 ). Compared to the reference compound 1 (Bz-Arg-Lys-Nle-NH 2 , IC 50 = 13.3 μM), a 4-fold higher inhibitory potential was observed with the incorporation of a C-terminal phenylglycine (compound 9, IC 50 = 3.3 μM). Second, we applied fragment merging of 9 with the previously reported thiazolidinedione peptide hybrid 33 (IC 50 = 2.5 μM). This approach led to the fusion of two inhibitor-fragments with micromolar affinity into a 20-fold more potent, competitive inhibitor of dengue protease. KEYWORDS: Dengue virus, protease inhibitor, peptide, fragment merging D engue virus (DENV), with its four common serotypes (DENV 1−4), is considered the most important diseasecausing arbovirus in tropical and subtropical regions and a major public health concern. A recent study estimates a global infection burden of 390 million cases in 2010, a more than 3-fold higher number than reported previously by the World Health Organization. 1,2 Increasing prevalence of dengue infections worldwide has been associated with the geographical spread of Aedes mosquitoes, the primary transmitting vector, probably as a result of global warming and climate changes. 3 Currently, vaccines or antiviral agents against DENV remain unavailable. Viral proteases are extremely relevant for the development of antiviral drugs. 4 Highly successful examples are the hepatitis C virus (HCV) NS3 protease inhibitors, such as boceprevir and telaprevir, 5 and the HIV protease inhibitors. 6 DENV protease is regarded as a similarly promising target for drug discovery efforts against dengue virus infections. 7 The enzyme is critical for the viral replication cycle. It posttranslationally cleaves the viral polyprotein, encoded by a single stranded RNA, into three structural and seven nonstructural (NS) proteins. The proteolytically competent NS3-NS2B complex consists of the NS3 serine protease domain and the hydrophilic core sequence of NS2B as cofactor. 8,9 Published inhibitors against DENV protease range from small molecule nonpeptidic inhibitors, 10−13 so far not capable of achieving sufficient target inhibition, to substrate-mimicking peptidic inhibitors. 14−18 The latter class benefits from improved molecular recognition because of its similarity to the natural substrate, which offers higher selectivity and activity, reaching the low micromolar range and even the nanomolar range when combined with an electrophilic warhead. 18 However, the promising in vitro binding affinities come at the expense of pharmacokinetic properties, such as membrane permeability and metabolic stability, which is challenged by ...

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“…The functional inhibition of viral NS proteins is mainly based on the anti-flavivirus drug development (10,20). In fact, the NS3 protein is multifunctional enzyme, which has three important regions including serine protease, helicase, and a nucleotide triphosphatase (7,21).…”

Section: Discussionmentioning

confidence: 99%

Antiviral Activity of Thiazolide Derivatives Against Dengue Virus in Huh-7 Cell Line

Yasmin

Yaqub

Khan

et al. 2017

Jundishapur J Microbiol

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Background: Dengue is one of the main health problems worldwide with dramatic increases in reported cases in the last few decades. Now, dengue is a major threat to half of the world's population and approximately 50 million infections occur every year. Objectives: The major aim of this study was to screen out different synthetic antiviral compounds against dengue virus. As treatments used for dengue virus infections are nonspecific and effectless, it is necessary to find specific antiviral compounds that may be helpful in the treatment of dengue fever. In cell culture models, thiazolides are active against anaerobic bacteria, protozoa, and a range of viruses. Methods: Samples from positive dengue fever patients were included in the study. For dengue serotype-2, serum samples were further confirmed by serotyping protocol. Results: After toxicological analysis, a sharp significant antiviral response was shown by compounds A and B decreasing the viral titer of serotype 2 as 46% and 53%, respectively. A greater antiviral activity was indicated by compound "B" against NS3 gene as compared to compound "A". Against NS3 gene, a comparable antiviral activity was observed for compounds "A" and "B". Conclusions: From our results, it can be concluded that compounds A and B (Thiazolides) as dengue antiviral drugs can reduce viral load in patients if their inhibitory effects are reproduced in vivo. To identify the specific active ingredients, further studies are required by using various techniques to determine the efficacy of these compounds in animal model.

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Ten years of dengue drug discovery: Progress and prospects

Cited by 326 publications

References 174 publications

Existing drugs as broad-spectrum and potent inhibitors for Zika virus by targeting NS2B-NS3 interaction

Existing drugs as broad-spectrum and potent inhibitors for Zika virus by targeting NS2B-NS3 interaction

C-Terminal Residue Optimization and Fragment Merging: Discovery of a Potent Peptide-Hybrid Inhibitor of Dengue Protease

Antiviral Activity of Thiazolide Derivatives Against Dengue Virus in Huh-7 Cell Line

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