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ISSN: 1948-593X
Journal of Bioanalysis & Biomedicine
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Review of Current Dengue Treatment and Therapeutics in Development

Fusco DN1* and Chung RT2
1Department of Medicine, Massachusetts General Hospital, Boston, MA 02114
2Director of Hepatology, Gastrointestinal Unit-GI Associates, USA
Corresponding Author : Dahlene Fusco, MD, PhD
Department of Medicine
Massachusetts General Hospital
Boston, MA 02114
E-mail: dnfusco@mgh.harvard.edu.
Received May 02, 2014; Accepted May 29, 2014; Published May 31, 2014
Citation: Fusco DN, Chung RT (2014) Review of Current Dengue Treatment and Therapeutics in Development. J Bioanal Biomed S8:002. doi:10.4172/1948-593X.S8-002
Copyright: 2014 Fusco DN, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Abstract

Dengue is an arthropod-borne flavivirus associated with hemorrhagic fever and hemorrhagic shock. Roughly one third of the world population lives at risk of dengue infection, and it is not possible to accurately predict which patients are at risk for severe or fatal infection. Currently, there is no treatment for dengue infection. However, several classes of agents are in under investigation as potential anti-dengue drugs, including direct antivirals, host modula - tors, and RNAi therapeutics. These anti-dengue drugs in development will be reviewed here.

Introduction
Dengue has been named one of the most important emerging infections in 2014 [1,2]. The geographic region at risk for dengue has increased fourfold over the past three decades, unprecedented for a vector-borne disease [2,3]. DENV is an arthropod-borne flavivirus associated with both hemorrhagic fever and hemorrhagic shock [4]. The classical clinical presentation of DENV is characterized by abrupt onset of headache, myalgia and high fever, in addition to arthralgia, retroorbital pain and hemorrhagic manifestations. The DENV hemorrhagic fever is characterized by fluid leakage into the intersistium. These symptoms are commonly seen in many other infectious diseases, which complicates diagnosis. DENV has also been implicated as a possible cause of multiple findings of end organ failure, including but not limited to: myocardial impairment (with arrhythmias and potential myocarditis), hepatitis with hepatic necrosis, maculopathy, rhabdomyolysis, multiple neurological manifestations, and fatal hemophagocytic lymphohistiocytosis [2,5-14]. 2.5 billion people live in DENV-endemic regions [4], and roughly 400 million infections occur per year with a case fatality rate exceeding 5-20% in some areas [15,16]. Over 100 countries are affected, including Europe and the United States [17]. As effective point of care (POC) diagnostics for malaria reach widespread utilization, the prevalence of non-malarial fevers, caused by dengue (DENV) and other infections, is increasingly noted in low and/or middle income countries (LMICs) [18,19]. DENV is endemic in many parts of Asia, and the DENV case frequency and fatalities in the Americas are increasing, where the total number of DENV cases reported quadrupled between the 1980s and 2000-2007 [7,17,20]. Furthermore, in recent years, infections in many LMICs are increasingly noted in adults, leading to significant number of work days lost and increasing costs to society [21].
Currently there is no specific treatment for DENV, recent hopeful vaccine candidates have just been deemed ineffective [22], and there is no prediction of complete vector control. However, rapid diagnosis followed by targeted vector control efforts decrease DENV transmission, and early detection followed by supportive care is reported to potentially decrease mortality rates from 5-20% to less than 1% [15,16,23]. In many endemic regions, when a surge of dengue infections is suspected, public health authorities will circulate notices in local newspapers, transmits announcements via radio, and even close schools and other public facilities during peaks of transmission in attempts to decrease likely exposure. Other preventive measures include use of insecticide sprays and elimination of all mosquito breeding grounds (areas of standing water are cleared, particularly in schools). While attempts at early diagnosis paired with prevention are helpful, the combined lack of effective treatment for dengue and increasing dengue transmission are worrisome.
This review will focus on treatments in various stages of development for dengue, organized based on treatment strategy, including direct acting antiviral approaches, RNAi approaches, and host-modulators, and will attempt to complement other recent helpful reviews [5,24]. This review will not cover progress being made toward the challenging fields of DENV vaccine design, vector-targeted interventions, of which there are many, anti-dengue therapeutic antibodies [25], or studies related to precise selection of supportive care measures including choice of rescuscitation fluid, corticosteroid administration [26] or platelet transfusion decisions [27,28]. An excellent updated review of DENV vaccine work has recently been published [29]. Additional helpful recent reviews describing DENV treatment strategies under development are cited [5,24,30-32].
Information included in this review was supported by a search of the PubMed database for articles published in the English language using the search term “dengue treatment”. In addition, bibliographies of the selected articles were reviewed for further relevant studies.
Methods of Bioanalysis for Anti-dengue Activity
Pre-clinical
Dengue is a positive stranded RNA virus with an 11kb genome, encoding a polyprotein precursor cleaved to generate at least 10 proteins, including three structural proteins (core, membrane associated protein, and envelope protein), and seven nonstructural proteins (NS1, NS2a, NS2b, NS3, NS4b, NS5) (Figure 1) [33] . DENV is transmitted by silent, urban mosquito vectors, including Aedes aegypti and A. albopictus, A. polynesiensis and A. scutellaris, to man [3]. Other modes of transmission include via blood products, organ transplant, and vertical transmission [34-37]. There are four serotypes (1-4) of dengue, and multiple genotypes. All four serotypes infect man, and infection with one serotype does not confer protection against another serotype. In contrast, infection with a second dengue serotype appears to be, in some cases, enhanced by pre-existing antibodies generated from primary infection. This phenomenon is referred to as antibody dependent enhancement, or ADE [5,38]. In man, the initial cellular target of dengue is thought to be dendritic cells, followed by lymphatic spread and then distribution to monocytes and macrophages [39,40]. The full host of cells infected in vivo remain a subject of investigation, but may also include hepatocytes, myocytes, and other cell types [6,41]. In the laboratory, dengue can be cultivated in C6/36 mosquito cells or Vero African green monkey kidney cells, though intracellular modifications of the virus are thought to differ in these two systems, and are also affected by passage number, and therefore must be monitored [42,43]. Laboratory isolates of dengue can be used to infect several human cell lines, including but not limited to HepaRG human hepatoma cells, Huh7 human hepatoma cells, human foreskin fibrosblasts, U937 and THP-1 myeloid cells, HeLa human cervical carcinoma cells [43,44]. In order to infect monocyte cell lines, pre-incubation of virus with antidengue antibody can be used to take advantage of antibody dependent enhancement (ADE), which increases the amount of dengue infecting each individual cell [5,38,43].
The level of dengue infectivity can then be monitored in vitro by multiple methods, including but not limited to plaque assay, qRT PCR, immunofluorescence, to identify compounds with antiviral activity. In addition to fully infectious dengue systems, in vitro reporter systems for dengue have been developed, and are also employed in assays seeking to identify dengue anti-virals [45-49]. The development of animal models of dengue virus (DENV) infection and disease has been challenging, since epidemic DENV does not naturally infect non-human species, but several models now exist, including the AG129 mouse (IFN alpha, beta, gamma knockout mouse), IFNAR1 knockout mouse, STAT2 knockout mouse, and, more recently, humanized BLT mouse [50-52].
Clinical
Clinical methods for evaluation of anti-dengue effects are in development. A major hurdle facing DENV clinical trials is the need for establishment of accurate diagnostic testing for case identification. However, current diagnostics for DENV available in the US and other high resource countries (PCR, IgM and IgG ELISA) are limited by a requirement for skilled workers, refrigeration, and specialized equipment [3,53]. Current point-of-care (POC) diagnostic tests for DENV are based on lateral flow detection of secreted DENV NS1 protein and IgM in blood/plasma/serum or saliva IgA [53,54]. NS1 assays are easy to use but limited in sensitivity, especially in secondary infections (common in endemic regions) [23,54], storage temperature, and cost [3,53]. IgG assays are limited in their inability to discriminate between recent and remote infection, and cannot detect early infection. Saliva IgA assays, alone, lack sensitivity during early primary DENV infection [23]. Because of these limitations, many LMIC sites with known endemic DENV are using clinical features, such as bleeding, leukopenia, or thrombocytopenia, and contextual epidemiological information to diagnose DENV at this time. Lack of precise diagnostic testing for DENV can lead to confusion in areas where malaria and yellow fever, which can include a similar presentation, are endemic, and can also serve as a barrier to regional participation in clinical trials, which currently represent the only potential mechanism of direct antiviral therapy, and further development and distribution of rapid diagnostic tests, coupled with test standardization, is in progress [53]. Recent clinical trials have included virologic (RT-PCR for DENV viral load and tests for secreted DENV NS-1 antigen) and immunologic measurements (multiple cytokine measurements). Because RT-PCR and cytokine assay technology may not be readily available at many dengue endemic sites, distribution of clinical trial efforts may be skewed. However, there is the possibility that increased DENV-drug design efforts will bring with them the benefit of technology transfer providing additional LMIC sites with these helpful resources.
Treatment
While current treatment for DENV is supportive care, there are multiple anti-DENV agents in various stages of development.
Agents in Development for Anti-Dengue Activity
Direct acting antivirals
RNA dependent RNA polymerase (NS5) inhibitors: N-sulfonylanthranilic acid derivatives were identified as DENV RdRp inhibitors through screening of one million compounds using a primer extension RdRp assay [1]. The identified hit was found to bind DENV NS5 at the site of entrance to the RNA tunnel. While this specific compound is not under further development, the concept of inhibiting polymerase through the tunnel as well as other allosteric pockets is being pursued.
Nucleoside Analogues: Balapiravir (RG1626) is a prodrug of a nucleoside (cytidine) analog, R1479, which itself must be triphosphorylated for conversion into active form. Balapiravir was initially developed for the treatment of HCV, but clinical trials were stopped due to toxicity during extended treatment courses (2-3 months) in combination with pegylated interferon and ribavirin [55- 57]. Because R1479 displayed in vitro anti dengue activity, and because of the shorter projected treatment duration for acute dengue infection (limiting toxicity), anti-dengue effects of balapiravir were explored in a phase II clinical trial [58]. An exploratory, dose-escalating, randomized placebo-controlled trial was conducted in adult male patients in Vietnam with dengue and <48 hours of fever. 32 subjects received five days of oral balapirivir (1500 or 3000 mg) for five days, and the medication was well tolerated. However, DENV viral loads, NS1 antigenemia, and fever clearance time were unaffected by treatment [58]. The authors accurately state that “although this trial, the first of its kind in dengue, does not support balapiravir as a candidate drug, it does establish a framework for antiviral treatment trials in dengue and provides the field with a clinically evaluated benchmark molecule” Subsequent analyses determined that when human PBMCs were preinfected with dengue (prior to balapiravir treatment), their ability to convert the prodrug balapiravir to the active, tri-phosphorylated nucleoside analog, R1479, form, was significantly impaired, resulting in decreased potency [59]. These in vitro studies also found that activation of NITD008, an adenosine based nucleoside analog [60], was less affected by dengue pre-infection, opening the possibility that further exploration of NITD008 may be warranted. A related compound, NITD203, was found to exhibit potent in vitro and in vivo anti-DENV efficacy, but satisfactory no-observable-adverse-effect levels could not be reached in 2 week in vivo toxicity studies [61].
Protease (NS2b-NS3) inhibitors: Recombinant retrocyclin 1. Rothan et al produced recombinant NS2B-NS3 protease in E. coli and identified recombinant retrocyclin 1, a cationic cyclic peptide theta defensing analogue with anti-HIV activity [62], as a potent DENV protease inhibitor [48].
BP13944: A screen of 60,000 chemical compounds in a DENV serotype 2 luciferase harboring replicon (BHK-21 cells) have recently identified BP13944, a quaternary ammonium salt, as an NS3 protease inhibitor [63].
α-ketoamides: Steuer et al designed an electrophilic trap for the serine component of the DENV NS2b-NS3 serine protease, and have identified α-ketoamides as DENV protease inhibitors [64].
Quinoline containing compounds: Using virtual screening for DENV protease inhibitors followed by scaffold hopping, to expand chemical diversity, then a DENV luciferase reporter replicon assay, Deng et al have described 17 new compounds with NS2b-NS3 protease inhibitor activity, which can now serve as potential lead structures for further discovery efforts [65].
NS4b inhibitor. Van Cleef et al recently screened the NIH Clinical Collection of drug-like small molecules for anti-DENV activity in HeLa cells harboring a subgenomic DENV2-replicon reporter and identified the δ opioid receptor antagonist SDM25N as potent DENV inhibitor [66].
Methyltransferase (NS5) inhibitors: Using a fragment-based drug discovery approach, Coutard et al recently screened 500 drug-like fragments by thermal-sift assay for binding to the DENV NS3 helicase or NS5 methyltransferase, and identified 7 validated MTase binders, each containing 5-6 membered aromatic rings [67].
Translation inhibitors. Wang et al performed a high throughput screen for reduction or elimination of DENV CPE and identified benzomorphan compounds that inhibit DENV through suppression of RNA translation and also inhibit DENV viremia in mice, though higher doses were limited by toxicity [68].
Capsid inhibitor: A high throughput small molecule screen with readout of DENV induced CPE was performed on over 200,000 compounds and identified ST-148 as a unique inhibitor of the DENV capsid protein with both in vitro and in vivo effects (AG129 mice) [69].
Peptide Inhibitors of Various DENV proteins: Several groups have recently proposed the use of peptide inhibitors to block DENV infection [70-76]. For example, Lok et al have identified the mimetic peptide DN59, which corresponds to a region of the dengue virus envelope protein, as an inhibitor of all four serotypes of dengue virus [70]. They have found that DN59 incubation with DENV virus particles leads to viral membrane disruption and release of DENV RNA from the viral particles, but was non-toxic to mammalian cells [70]. In another study, 2 synthetic antiviral peptides were designed against target domain III of DENV2 envelope protein, and were found to exhibit significant DENV inhibition in vitro [73]. Prusis et al designed 45 peptide inhibitors against the DENV NS2b-NS3 protease and identified the tetrapeptide WCW-NH2 as an inhibitor of DENV 1-4 proteases [74].
Host Modulators
The compact 11 kb genome of DENV forces DENV to rely on multiple host factors for replication. This property can be exploited in attempts to inhibit viral replication through deprivation of these required host factors, or dependency factors. This strategy, targeting host factors to impede dengue viral infection, has recently been reviewed [30].
Ribavirin
Ribavirin is a broad acting inhibitor of RNA and DNA viruses. It is a synthetic guanosine analog which inhibits inosine monophosphate dehydrogenase with resulting GTP pool depletion [77], but has multiple additional proposed mechanisms of action, including up regulation of antiviral genes [78,79]. Ribavirin use has been limited by toxicity of both aerosolized and oral formulations, decreasing its clinical efficacy [80]. The complete compendium of downstream effectors of ribavirin antiviral effects is unknown. Ribavirin has been shown to have anti-DENV properties in several cell lines and primary cells [81,82], and is often used as a positive control in cell culture assays for anti-DENV compounds. However, ribavirin was not demonstrated to have anti-DENV activity in either a mouse (AG129) or a primate model of DENV viremia [83,84]. However, more recent studies have described potentiation of sub-effective dose alpha glucosidase inhibitor CM-10-18 by ribavirin in AG129 mice, underscoring a possible role for ribavirin as a treatment enhancer, similar to its role in peg-IFN treatment of HCV [85].
Mycophenolic Acid
The immunosuppressive agent mycophenolic acid (MPA), a nonnucleoside inhibitor of IMP dehydrogenase, has also been shown to inhibit dengue in cell culture, reproduced in four hepatoma cell lines, by preventing synthesis and accumulation of viral RNA [86].
Agents that Target Host Mediated Post Translational Modifications
α Glucosidase inhibitors
Flavivirus assembly occurs at the host endoplasmic reticulum where DENV structural proteins prM and E colocalize to form an immature particle in the ER lumen, where a high mannose carbohydrate, (Glc)3(Man)9(GlcNAc)2, is added in the ER to specific asparagine residues on the prM and E proteins [87,88]. This carbohydrate is then modified by host α-glucosidases to generate N-linked glycans that lack the terminal α(1,2) and α(1,3) glucose residues [89]. It has been found that trimming these N-linked carbohydrates in the ER may be required for DENV assembly or secretion of DEN [88,90,91]. α glucosidase inhibitors include the naturally occurring iminosugar castanospermine and also deoxynojirimycin, isolated from Bacillus. Castanospermine was found to inhibit infection with all four DENV serotypes in vitro, and also to prevent dengue mortality in an A/J DENV mouse model [88]. More recently, a pro-drug of castanospermine, 6-O-butanoyl castanospermine, or celgosivir, has found to fully protect AG129 mice from lethal infection with mouse adapted DENV when given up to 48h following infection, and pharmacokinetic studies showed that celgosir is rapidly metabolized to castanospermine in mice [92,93]. A randomized, double-blind, placebo-controlled, phase 1b clinical study to evaluate the activity, pharmacokinetics, safety and tolerability of celgosivir was conducted in adults with confirmed dengue fever in Singapore between 2012 and 2013 (ClinicalTrials.gov identifier NCT01619969). Results of that trial are anxiously awaited.
In parallel, another group examined the anti-DENV effects of the iminosugar drug UV-4, derived from deoxynojirimycin, in vivo in the AG129 mouse model, and found that UV-4 reduced mortality, DENV viremia, tissue levels of viral RNA, and virus induced cytokines, and that UV-4 also decreased mortality in an ADE model of secondary DENV infection [94]. Importantly, UV-4 treatment could be delayed up to 48 h in this mouse model, indicating its potential role as a therapeutic, though the therapeutic window is narrow because if administered at 72 h post infection, antiviral effects were no longer present [94]. In an outbreak setting, such early or possibly pre-emptive treatment could still be both feasible and useful. A phase I study of UV-4 opened in February 2014 (NCT02061358).
Other alpha glucosidase inhibitors, including N-alkyldeoxynojirmcin derivatives [95] and α glucosidase substrate mimics, such as CM 9 78 and CM 10 18, are in development [85,96]. Perhaps one of the most exciting recent developments in the field, a recent study of co administration of the α glucosidase inhibitor CM- 1018 with ribavirin led to significant reduction of viremia in mice [85], for the first time providing data that the in vitro anti-DENV effects of ribavirin can be unlocked in vivo in the appropriate setting.
Cyclosporine blocks DENV NS5 interaction with the host dependency factor, cyclophilin, leading to DENV inhibition [97].
Lovastatin
Statins are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, used for lipid lowering and mortality reduction in cardiovascular disease, and have an excellent safety profile [98,99]. Statins have been found to exhibit anti-DENV properties in both cell culture and mouse models [100-102]. A clinical trial examining the safety and antiviral properties of lovastatin in adult patients is now ongoing in Vietnam [103].
Heparin and Heparan Sulfate
It is interesting to note that highly sulfated heparan sulfate is involved in initial interactions between the DENV E glycoprotein and the host cell, and heparin and heparan sulfate like molecules have been found to have anti-DENV properties [104-111]. The important complexities of DENV infection and host coagulation state will not be explored in this review.
Vitamin D
Treatment of both monocytic (U937) and hepatic (Huh 7) cells with 1α, 25-dihydroxy-vitamin D3 was associated with decreased levels of DENV infection [112].
Host Kinase Inhibitors
Using an immunofluorescence imagebased assay suitable for identification of small molecule inhibitors of dengue virus infection and replication, Chu et al identified AZD0530 and dasatinib, inhibitors of Src and Abl kinases, as potent DENV inhibitors. More recently, this group has determined that AZD0530 and dasatinib inhibit DENV viral RNA replication through inhibition of the host dependency factor, Fyn kinase [113]. Of note, AZD0530 (saracatinib) is in advanced clinical trials, pending FDA approval, while dasatinib is FDA approved.
Viral sensor (RIG-I and TLR3) agonists
The innate immune system includes detection of viral RNA by the helicase domain of RIG-I [114,115]. A synthetic 5’ triphosphate (5’ppp) RNA was designed to stimulate this host innate immune response as an antiviral therapeutic, and was found to have anti DENV effects when transfected into A549 cells as well as primary human monocytes prior to DENV infection [116]. Along a similar vein, Diwaker et al have recently identified the RIG-I inducer Rhodiola as an inhibitor of DENV in human peripheral blood mononuclear cells and the human monocytic cell THP1 cell line, when administered 2 hours after DENV infection [117]. Et al showed that TLR3 activation through administration of the dsRNA compound PIKA prior to DENV infection decreased DENV infection of HepG2 cells [118].
Interferon
The type 1 IFNs, including IFNα, are among the broadest acting antiviral therapeutics known [119]. IFNα is a current component of anti-HCV therapy and has also been used with success for hepatitis B, severe acute respiratory syndrome, and WNV ([120-122]). Severe viral infection is often the result of subversion of the host immune response, rendering that response ineffective. A major common pathway of viral immune escape is suppression of the IFNα pathway (Figure 2) [33,123-143]. While IFN escape mechanisms vary from virus to virus, activation of IFN effectors downstream of viral subversion may identify common drug targets for restoration of an effective host antiviral response [30,144,145] (Figure 2). Although it will likely soon be possible to reduce reliance on IFNα in HCV treatment regimens [146-149], understanding the mechanism of this broad-acting antiviral will inform design of agents active against many viruses, such as DENV, that antagonize IFNα and for which no current treatment is available [124,126,132,134-137,150]. Elucidating the antiviral mechanism(s) of IFNα will also improve understanding of host-virus interactions, including variable human susceptibility to viruses and response to IFN or potential IFN-related therapies
IEG Activation will Circumvent Viral Subversion of IFN Signaling
Type I IFN (α and/or β) binds to the type 1 IFN receptor (IFNAR1/2), which interacts with JAK1/TYK2, which can be followed by activation of STAT1 and 2 and subsequent formation of the heterotrimeric complex IFN–stimulated gene factor 3, or ISGF3 (consisting of STAT1, STAT2, IRF9) (Figure 2) [123,144]. ISGF3 then translocates to the nucleus, and directs transcription of hundreds of IFN stimulated genes (ISGs) through an IFN stimulated response element (ISRE) [123]. When intact, this system is highly effective in limiting viral infection. However, many pathogenic viruses have evolved mechanisms to escape the type I IFN response [33,132,134-136,150,151]. For example, HCV inactivates a host protein required for endogenous IFN production (mitochondrial antiviral signaling protein (MAVS), also known as IPS-1 and VISA) [152,153]. Downstream of IFN production, HCV also inhibits the activity of IFN (endogenous or exogenous) [154].
In general, IFNα can successfully inhibit DENV if given preinfection, but not post-infection, due to DENV mediated suppression of early members of the IFN signaling pathway [140,155], though some antiviral effect was observed in post-infection administration of PEGrIFN- alpha-2a, which significantly lowered daily viremia levels and improved virus clearance, in rhesus monkeys [156] . Defining where viruses block, or subvert, the host IFN response can inform design of antivirals that act downstream of that block. In preliminary studies, we have identified 120 host antiviral candidates in a whole genome siRNA screen for HCV IEGs [44]. In addition, we have screened these 120 HCV IEG knockdowns for rescue of DENV from IFN in HeLa cells and have identified a subset of 45 HCV/DENV IEGs. Among our 45 HCV/DENV IEGs, we detected 6 known ISGs, including JAK1 and STAT2. While JAK1 and STAT2 lie proximal to likely subversion by Flaviridae (Figure 2), the remaining 4 DENV/HCV IEG/ISGs are likely downstream of this block, and may serve as candidates for IEG activation. Broad-acting IEG activation fits with criteria for identifying high-value targets for therapeutic intervention by (1) overcoming viral ability to inhibit IFN action or (2) acting downstream of the virusmediated IFN block. Because of their downstream location, such therapeutics could have fewer systemic effects than IFN itself, which would contribute to improved tolerability and therapeutic index. As host rather than virally targeted agents, these therapeutics are predicted to have a high barrier to viral resistance.
D4 dopamine receptor antagonists
Smith et al have identified a class of tricyclic small molecule compounds, the dihydrobenzothiepines (DHBTs), in a high throughput small molecule screen for DENV-2 inhibitors, using high content immunofluorescent assay readout in HEK293T cells [157,158]. They further determined that SKI-417616, a highly active DHBT, inhibited all 4 DENV serotypes in vitro at an early event in the DENV lifecycle, and identified the mechanism of activity as host D4 dopamine receptor inhibition. The authors suggest that, in vivo, macrophage-expressed dopamine receptors may be targettable DENV dependency factors
Ivermectin
The anti-helminthic drug ivermectin has been identified as an inhibitor of the nuclear importer importin α/β. Because DENV NS5 polymerase activity requires importin α/β, anti-viral properties of ivermectin were explored, and revealed that pre-treatment with ivermectin inhibited DENV infection of Vero cells [159]. Supporting NS5 inhibitor effects of ivermectin, Tay et al. have found that ivermectin pretreatment strongly inhibits the nuclear localization of NS5 during DENV 1, 2 infection of BHK-21 or Huh-7 cells, along with inhibition of DENV infection levels [160]. At the same time, Mastrangelo et al identified ivermectin as a DENV NS3 helicase inhibitor using an in vitro modelled helicase inhibition assay, and further confirmed ivermectin anti-DENV activity, though only for virus yield reduction (qRT-PCR) and less so for CPE reduction [161].
Pentoxifylline
A small clinical trial of the TNFa inhibitor, pentoxifylline, showed a potential decrease in mean length of ICU stay and decreased TNFa levels, though viral parameters were not assessed [162].
Chloroquine
Chloroquine is an inexpensive, widely available, well-tolerated lysosomotropic 4-amino-quinoline derivative, which is well known as an anti-malarial drug but also possesses in vitro anti-viral activity, including anti-DENV activity, potentially related to its effect of increasing endosomal pH [163,164]. In vitro, treatment with chloroquine caused a dose-dependent reduction of DV-1 infectivity in THP/DC-SIGN cells [165]. A clinical trial of anti-DENV efficacy of chloroquine was performed in Vietnam, where 154 adult patients with suspected dengue received 3d chloroquine versus placebo. While a trend toward lower incidence of dengue hemorrhagic fever was detected, chloroquine did not reduce the duration of DENV viremia or NS1 antigenemia [166].
Amodiaquine
The quinoline derivative amodiaquine was recently identified in a replicon based screen for anti-DENV agents, and confirmed to have anti-DENV activity in DENV2 plaque assays and qRT PCR assaying for both intracellular and extracellular DENV levels [46].
RNAi
RNA interference, or RNAi, is a gene silencing process which degrades target RNA in a sequence specific fashion. RNAi has been proposed as a strategy to directly inhibit viral infections, including DENV [167-170]. One group showed that use of dendritic celltargeting peptide mediated delivery of siRNA against a conserved sequence in the DENV envelope effectively suppressed DENV replication in macrophages and monocytes [171]. In addition to RNAimediated suppression of DENV itself, RNAi-mediated suppression of viral dependency factors, or factor required by the virus for productive infection, has been shown to inhibit DENV [172,173]. There are currently no RNAi agents registered under clinicaltrials.gov when searched with dengue
Interestingly, it has recently been found that the DENV NS4B protein of all four DENV serotypes acts as a suppressor of human intracellular RNAi machinery, including Dicer, Drosha, Ago1, and Ago2, as well as many human microRNAs [174].
Morpholinos
Taking advantage of the RNA-RNA or RNA–protein interactions required for DENV replication, antisense peptide-conjugated phosphorodiamidate morpholino oligomers (P-PMOs) have be designed to sterically interfere with these interactions [175-178]. Holden et al. evaluated the mechanism and effectiveness of DEN 5’ stem loop, DEN 3’ cyclization sequence, and one more novel morphilino complementary to the top of the DENV 3’ stem loop. They found that the 5’SL P-PMO blocked DENV viral translation, the 3’CX P-PMO blocked viral RNA synthesis, and the novel 3’ SLT P-PMO blocked both viral translation and RNA synthesis, and could potentially be useful as therapeutics in human infection
Other Compounds
Other agents that have been suggested to display anti-dengue activity include geneticin, an aminoglycoside antibiotic, which has been found to have the unique property, among aminoglycosides, of inhibiting DENV [179] and FCI 106, a compound of unknown mechanism identified in a screen for anti-Ebola agents, which has also been found to have anti-DENV activity, in DC-SIGN cells [180].
Medicinal plant derivatives
There is a significant amount of research dedicated to hypothesis– driven and practice-based identification of naturally occurring compounds with anti-dengue properties. While this literature will not be reviewed extensively here, several recent references are indicated [181- 187]. It is important to note that many of the compounds examined in these studies are selected because they are already in use against dengue in traditional settings, underscoring the need to examine their effect on dengue-related outcomes, regardless of whether they will be assessed for drug development.
Summary
In summary, dengue virus has emerged as an increasingly worrisome arboviral disease, with 2.5 billion people currently living in regions at risk of disease, and innumerable others exposed through travel, with no realistic optimism of near-term vaccine or vector control, and incomplete understanding of factors predicting who will succumb to fatal infection. There are multiple leads for antiviral design advancing through the therapeutic development pipeline, and clinical trials are beginning. Major challenges ahead will include identification of compounds that validate in vivo [68], exhibit a highly favorable safety profile, are active beyond the earliest hours of infection, are inexpensive, and unlikely to be overcome by viral resistance. There is a significant amount of work to be done
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