Table 1 Main compounds used as flavivirus inhibitors

E

NITD-448

DENV

Lim et al., 2013a [38]

NITD-448 inhibited E protein-mediated membrane fusión as well as DENV-2 infection. Due to the large molecular weight of this compound, por selectivity, and pharmacokinetic properties, this compound series was not further pursued.

Compound 6

DENV

Lim et al., 2013a [38]

Compound 6 has low potency and high plasma protein-binding activity due to lipophilicity that prevented further development of the compound.

P02

DENV, YFV

Zhou et al., 2008 [44],

Lim et al., 2013a [38]

P02 inhibits viral replication at micromolar concentrations. No follow-up studies have been reported for this compound.

D02, D04 and D05

DENV

Zhou et al.,2008 [44]

D02, D04 and D05 inhibit the virus life cycle. This compounds reduced viral replication activity.

A5

DENV, YFV, WNV

Lim et al., 2013a [38]

A5 has low micromolar activity against DENV, WNV, and YFV. No follow-up studies have been reported for this compound.

1662G07

DENV

Lim et al., 2013a [38]

SAR studies led to analogs with activity against DENV-2, some activity against DENV-4, but weak activity against DENV-1 and −3. The antiviral spectrum of this compound needs to be evaluated.

Castanosper-mine

DENV

Lim et al., 2013a [38]

Castanospermine inhibit DENV replication, disrupting folding of DENV structural proteins prM and E, as well as NS1.

Celgosivir

DENV

Lim et al., 2013a [38]

Celgosivir inhibit DENV replication, disrupting folding of DENV structural proteins prM and E, as well as NS1. A phase Ib clinical trial is currently ongoing to evaluate the activity, pharmacokinetics, safety, and tolerability of Celgosivir in dengue patients.

Peptide DN59

DENV

Lok et al., 2012; [46]

Badani et al., 2014 [45]

Peptide DN59 inhibits the infectivity of flaviviruses by releasing their genome.

C

ST-148

DENV

Lim et al., 2013a [38]

ST-148 has limited oral bioavailability. Greater preclinical development is warranted.

NS3- ProteasE

Bowman-Birk inhibitor

DENV

Bollati et al., 2010 [2]

A starting point is provided for the design of specific inhibitors. The current situation of this compounds is unknown.

BP13944

DENV

Yang et al.,2014 [48]

BP13944 inhibited viral replication or RNA synthesis in all four DENV serotypes. Further work is required to determine the interaction mechanism.

Compound 32 (keto amides)

DENV

Steuer et al., 2011 [49]

An inhibitory effect on DENV replication was determined in a dose-dependent manner. Cytotoxicity in cell culture is unknown.

Peptide WCW-NH2

DENV

Prusis et al., 2013 [50]

Peptide WCW-NH2 inhibited protease in the four serotypes.

ARDP0006 and ARDP0009

DENV

Tonlimson and Watowich, 2011 [51]

ARDP0006 and ARDP0009 inhibited DENV-2 virus replication in cell culture. Promising compounds for future research.

Aprotinin

DENV

Noble et al., 2010 [53]

Aprotinin envelops the enzyme and prevents the substrate from accessing the protease active site.

NS3- HelicasE

Halogenated benztrioles

WNV

Sampath and Padmanabhan 2009 [3]

Halogenated benztrioles were good, and selective inhibitor of the West Nile virus.

Ivermectin

DENV, JEV, YFV

Mastrangelo et al., 2012 [55]; Sweeney et al., 2015 [57]

Promising compound as the first specific therapy against flaviviruses (patent application EP2010/065880).

ST-610

DENV

Lim et al., 2013a [38]; Sweeney et al., 2015 [57]

ST610 potently and selectively inhibited all four DENV serotypes in cell culture. For future trials, the pharmacokinetic properties of this compound should be improved.

Suramin

DENV

Basavannacharya, Vasudeban, 2014 [58]; Sweeney et al., 2015 [57]

Suramin acted as a potent NS3 helicase inhibitor of dengue virus by a non-competitive mode of inhibition.

Analogues ML283

DENV

Sweeney et al., 2015 [57]

Analogues ML28331 were potent inhibitors of DENV NS3- catalyzed ATP hydrolysis. These trials serve as a tool to find more inhibitory compounds.

Pyrrolone

DENV, WNV

Sweeney et al., 2015 [57]

Pyrrolone inhibited DENV replicon and WNV replication in cell culture. These trials serve as a tool to find more inhibitory compounds.

NS4 B

SDM25N

DENV

Van Cleef et al., 2013 [59]

SDM25N showed antiviral activity against wild-type DENV2 in both Hela and BHK-21 cells, but not in the C6/36 cell line. Further studies are required.

NITD-618

DENV, WNV, YFV

Van Cleef et al., 2013 [59]; Lim et al., 2013a [38]

The high lipophilicity of NITD-618 resulted in poor pharmacokinetic properties which hindered testing its activity against DENV in AG129 mice. It was inactive against WNV and YFV.

NS5-metHYl-transfe-rasE

Sinefungin

DENV, WNV

Lim et al., 2015 [61]

The affinity for Sinefungin is approximately six times higher than for SAM. Sinefungin is non-cell permeable. This compound does not show progress

S-adenosyl homocysteine

DENV

Lim et al., 2015 [61]

S-adenosyl homocysteine is non-cell permeable. This compound does not show progress.

Compound 10

DENV

Lim et al., 2013a [38] 

Lim et al., 2015 [61]

Compound 10 is non-cell permeable. This compound does not show progress.

GMP

DENV

Lim et al.,2015 [61]

GMP is non-cell permeable. This compound does not show progress.

BG-323

DENV

Lim et al., 2015 [61]

BG-323 showed in vitro inhibition of DENV. The current situation of this compound is unknown.

Aurintricarboxylic acid

DENV, YFV

Lim et al., 2015 [61]

Aurintricarboxylic acid inhibited the DENV MTase and YFV. The current situation of this compound is unknown.

4-HPR

DENV

Lim et al. 2015 [61];

Lai et al., 2017 [10]

4-HPR showed efficacy in DENV mouse models. Promising compound. Due to its tolerable human profile, it could be a treatment for patients with DENV.

Ivermectin

DENV

Lim et al., 2013a [38];

Lim et al., 2015 [61];

Lai et al., 2017 [10]

Ivermectin is a promising compound. The estimated study completion date was February 2016 (ClinicalTrials.gov identifier: NCT02045069).

Ribavirin

DENV

Lim et al., 2013a [38]

Ribavirin has limited use due to its toxicity, thus, decreasing its clinical effectiveness.

NS5-polYmera-sE

N-(4 hydroxy-phenyl) retinamide

DENV

Lim et al., 2015 [61]

N-(4-hydroxyphenyl) retinamide did not affect NS5 RdRp activity, but inhibited DENV replication in cells.

Ivermectin

DENV

Tay et al., 2013 [56];

Lim et al., 2015 [61]

Ivermectin did not affect NS5 RdRp activity, but inhibited DENV replication in cells. However, problems related to the toxicity of ivermectin may present significant challenges for its potential use in anti-DENV therapy.

7-deaza-2’-C methyladeno-sine (7DMA)

ZIKV

Zmurko et al., 2016 [67]

7DMA was shown to reduce viremia and delay the time to disease progression in virus-infected mice.

3’dGTP

DENV

Malet et al., 2008 [8]

3’dGTP showed low micromolar IC50 values in in vitro DENV2 RdRp activity tests using a poly(rC) template.

ddGTP

DENV

Malet et al., 2008 [8]

ddGTP showed low micromolar IC50 values in in vitro DENV2 RdRp activity tests using a poly(rC) template.

3’dioxolano 3’dGTP

DENV

Malet et al., 2008 [8]

3’dioxolano 3’dGTP showed low micromolar IC50 values in in vitro DENV2 RdRp activity tests using a poly(rC) template.

2’-O-metil GTP

DENV

Malet et al., 2008 [8]

2’-O-metil GTP showed low micromolar IC50 values in in vitro DENV2 RdRp activity tests using a poly(rC) template.

HPA 23

DENV

Malet et al., 2008 [8]

HPA 23 Inhibited virus replication in Vero cells. The current situation of this compound is unknown.

NITD 008

DENV, WNV, YFV

Lim et al., 2013a [38];

Caillet et al., 2014 [30]

Severe side-effects were observed in rats and dogs. These results led to the termination of NITD-008 for further development for DENV treatment.

NITD 203

DENV, WNV, YFV

Calleit et al., 2014 [30]

NITD 203 showed in vivo toxicity after 2 weeks of administration in rats and dogs.

Balapiravir

DENV

Lim et al., 2015 [61]

Balapiravir failed to be effective for patients with DENV. No efficacy was found in phase II Clinical trial.

N-sulfonyl-anthranilic acid derivatives

DENV

Niyomrattanakit et al., 2010 [17]

NITD-29 inhibited DENV-2 in a virus titer reduction assay, neither NITD-1 nor NITD-2 exhibited any antiviral activity in cell culture.

2’E-7D-ATP

DENV

Latour et al., 2010 [18];

De Burghgraeve et al. 2013 [64]

2’E-7D-ATP was able to inhibit all DENV serotype replication. However, the catalytic efficiency of incorporating this molecule was 10-fold lower than that of ATP.

Modified tri-phenylmethyl nucleosides

DENV, YFV

Chatelain et al., 2013 [23]

The finding of these lipophilic structures should stimulate the interest for further structure activity research.

2’,5’-bis-O-tritylated uridine

DENV, YFV

Chatelain et al., 2013 [23]

2’,5’-bis-O-tritylated uridine proved to be successful. This discovery was followed by synthesis of a series of close analogues, as a first attempt for setting up a structure activity relationship (SAR).

3’,5’-bis-O-tritylated uridine analogues

DENV, YFV

Chatelain et al., 2013 [23];

Saudi et al., 2014a [25]

These simple lipophilic structures show strong YFV inhibiting properties, further structure activity research is warranted.

Compound 27, 29i and 29

DENV

Lim et al., 2016 [11]

Compound 27 inhibted all four serotypes when inhibition studies were performed with clinical isolates of DENV1-4. Compound 29i was the next most potent compound and 29 displayed relatively lower cellular inhibition.

no speCIFIC ACTION

Lycorine

WNV, YFV, DENV

Zou et al., 2009 [21]; Lim et al., 2013a [38];

Lycorine potently inhibited flaviviruses in cell culture, it was reported to reduce viral titers of WNV, DENV, and YFV mainly through suppression of viral RNA replication.

Amodiaquine

DENV

Boonyasuppayakorn et al., 2014 [33]

Amodiaquine inhibited DENV2 infectivity measured by plaque assay.

AS101

WNV

Indenbaum et al., 2012 [69]

AS101 had a potential preventive and therapeutic effect against WNV infection.

7-deaza-2’-C-acetylene-adenosine

DENV

De Burghgraeve et al., 2013 [64]

7-deaza-2’-C-acetylene-adenosine showed anti-DENV activity in cell culture and significantly reduced viremia in a mouse model.

I45DC

DENV, YFV

Saudi et al., 2014b [70]

I45DC had a high dengue virus inhibitory activity.

P23DCs derivatives

DENV, YFV

Saudi et al., 2014b [70]

P23DCs derivatives had potent DENV and YFV inhibitory properties.

Favipiravir

(T-705)

FYV, WNV

De Burghgraeve et al., 2013 [64];

Furuta et al., 2013 [71]

Lack of good in vitro antiviral activity of Favipiravir (T-705). Considerably higher concentrations of this compound were required.

T-1105 and

T-1106

FYV, WNV

Furuta et al., 2009 [72]

There are insufficient data to clarify the reason why the in vivo antiviral effect of T-1106 did not correspond to its in vitro activity and why there were such differences in antiviral activities between T-1106 and T-705. T-1106 can be a useful drug for YFV in humans.

NITD008

ZIKV

Deng et al., 2016 [73];

Xie et al., 2016 [43];

Adcock et al., 2017 [27]

NITD008 showed potent anti-ZIKV activity. It could serve as a reference inhibitor for future drug screen and discovery.

ZINC33683341

and ZINC49605556

ZIKV

Sandun et al., 2016 [74]

The results obtained from these assays are a starting point for drug discovery targeting Zika virus and other emerging pathogens.