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These glycoforms have human-like biantennary N-glycans with terminal N-acetylglucosamine, resulting in a structure similar to that of human mAbs. Hence, these are beneficial for humans Both RNA and DNA viruses have been modified to serve as plant-based vectors for the expression of heterologous proteins. Bean yellow dwarf virus, a single stranded-DNA virus, can replicate inside the nucleus of plant cells using their cellular machinery.

A vector containing deletions in the coat-encoding genes and gene for the desired antigen may be inserted to form an expression cassette. The delivery of vectors to plants is Agrobacterium -mediated In this context, it is noteworthy that lettuce acts as a very good host for the process of agroinfiltration. In lettuce cells, Agrobacterium tumefaciens has been used for delivering viral vectors This quantity is similar to that generated in magnICON expression system The plant-derived approach to vaccine development is attractive because of the large amount of transient proteins that can be expressed, with the potential for use during high demand for therapeutics and prophylactics Advances in the field of vector expression like plant transient expression system and associated host cell engineering and manufacturing processes paved way for developing biopharmaceutical proteins and therapeutics in commercial basis.

The great potentials of such novel approaches have been exploited for evolving therapeutics to counter emerging pandemics of EBOV and influenza that is evidenced from the production of experimental ZMapp antibodies An overview of various types of vaccines for countering EVD is presented in Table 1 and depicted in Figure 1. Figure 1. Various vaccine platforms under progress for the development of a successful Ebola virus EBOV vaccine.

Platforms like inactivated vaccine, DNA vaccine, virus-like particles, virus-like replicon particles VRPs , plant-based vaccine, and recombinant viral-vectored vaccines are available. Momentous leap has been witnessed toward the designing of efficacious EBOV drugs and therapeutics during the short span of only few years, even though the efficacy of several biologicals and vaccines were evaluated during the recent West African outbreak, it remained elusive to ratify a licensed EBOV disease treatment regimen Management of suspected or confirmed EVD patients includes quarantine, symptomatic, and supportive treatments, including fluid replacement, electrolyte imbalance correction, treating complicated infections, and preventing shock For mitigation of the huge fluid loss and resultant hypovolemia, oral rehydration solutions should be provided adequately and if required anti-diarrheal and anti-emetic drugs need to be administered Brincidofovir, a drug used to treat dsDNA viruses such as adenovirus, herpesviruses, orthopoxviruses, papillomavirus, and polyomaviruses, was approved for emergency treatment of two patients with EBOV infection; however, the clinical efficacy of the drug is unknown Many drugs are being tested to identify specific antiviral drugs to treat EBOV, and new drug candidates are being developed by researchers worldwide 26 , , Favipiravir T , an antiviral drug found useful in treating influenza, has been studied and found effective against EBOV — Insertional mutagenesis, a high-throughput method to identify genes responsible for virus replication, can be used to develop drug candidates Molecular docking experiments with EBOV GPs can be used for drug designing and the development of therapeutics , Novel flexible nucleosides called fleximers were found to be effective against recombinant EBOV in Huh7 cells Ribavirin antiviral can be recommended for the treatment of EBOV, since in mouse and monkey models, treatment with ribavirin delayed the death and increased survival rate However, adverse effects associated with its use may limit ribavirin use Lamivudine, an anti-retroviral drug, has been tested by Liberian doctor on 15 EBOV patients with survival of 13 patients However, study by Cong et al.

Similar results were obtained by Hensley et al. Hence, the use of lamivudine may not be advocated. Gossypetin and Taxifolin the two flavonoids of top ranks showed higher docking scores for every EBOV receptor A virtual analysis of more phytochemicals could help to identify plant-derived products with comparatively higher efficacy and lower toxicity. Using molecular dynamics simulations, graphene sheets are found to associate strongly with VP40 matrix protein of EBOV and disrupt VP40 hexamer—hexamer association, crucial to form virus matrix, thereby graphene and similar nanopolymers may be used as therapy or at least disinfectant to reduce the risk of transmission at time of epidemic The potential of retro-type drugs molecules that block the retrograde trafficking of bacterial and plant toxins within mammalian cells must be explored for designing novel therapy against filovirus Retro-2 along with its other two derivatives, Retro The derivatives were shown to be more potent inhibitors of filoviral penetration, replication, and progression when compared with their parent compound, as evidenced by pseudo-typed virus assays The cell entry of EBOV involves virus binding to the cell surface receptors followed by internalization through macropinocytosis, processing by endosomal proteases, and transport to Niemann—Pick C1 NPC1; an internal receptor for EBOV containing endolysosomes.

Phosphatidylinositolphosphate 5-kinase is essential for maturation of endosome, a critical step to the EBOV infection In vitro studies using apilimod, an antagonist of phosphatidylinositolphosphate 5-kinase, showed inhibition of EBOV by blocking the viral particle trafficking to NPC1 containing endolysosomes Supportive treatments like oral rehydration therapy are recommended for children under 5 years of age The web server Ebola VCR has been developed, with details available for the development of suitable therapeutic agents Numerous treatment options for EVD are discussed below.

Ebola virus possesses only one surface protein and is responsible for both the receptor binding and fusion of virus-to-host cell endosomal membrane. The infection initiated with the binding of EBOV glycoprotein to lectin receptors and internalization of virus majorly through macropinocytosis and as alternative mechanism through clathrin-dependent endocytosis Possibly this proteolytic cleavage exposes the putative receptor-binding region that interacts with NPC1, a receptor facilitating the filovirus entry TIM-1 receptors directly interact with phosphatidylserine on the viral envelope, suggestive of GP independent virus attachment onto the cells.

Other phosphatidylserine interacting proteins like TIM-4 and Axl a receptor tyrosine kinase also have been demonstrated to enhance the infection of several enveloped virus. Tetrandrin is a potent drug that inhibits the EBOV entry into the cells Two estrogen receptor drugs, clomiphene and toremifene, have been reported to hinder EBOV infection in mice by blocking cell entry and fusion with host cells Amiodarone, an ion channel blocker, has been found to inhibit EBOV entry into cells , Dendrimers and fullerene C 60 have unique symmetrical properties and were recently found effective in inhibiting EBOV entry in vitro Clarithromycin, an antibiotic, inhibits the release of calcium stimulated by nicotinic acid adenine dinucleotide phosphate from lysosome and exhibit anti-EBOV activity.

Alike clarithromycin, posaconazole, an anti-fungal agent also shows similar anti-EBOV activity. In addition, it also inhibits the functions of NPC1 protein and acid sphingomyelinase activity. Both drugs, i. The drug 5- N -ethyl- N -isopropyl amiloride inhibits the process of macropinocytosis a process required for uptake of large filamentous virions, like EBOV and thus interferes with the viral entry into the cell. The assay was based on cell entry of HIVbased surrogate in well format. The time-of-addition studies suggested that EBOV entry is stopped at level of initial attachment prior to fusion of virus and cell membrane Thus, proteases may be a good target for the inhibition of EBOV replication.

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One study showed that, using a synthetic serine protease inhibitor, nafamostat mesilate NM , caused a reduction in CatB release in rat pancreases. Thus, this drug should be examined in clinical trials to be approved for the treatment of EVD Chemically modified human serum albumin with 3-hydroxyphthalic anhydride HP-HSA has been demonstrated with the potential of a therapeutic candidate in resisting the EBOV infection Convalescent serum by definition contains immunoglobulins IgM and IgG but is devoid of red blood cells and clotting factors.

Transfusing convalescent whole blood and convalescent plasma from disease survivors has been found to neutralize EBOV and reduce its load; thereafter, the immune response of the patient can provide protection against EBOV , Protection is conferred in NHPs through antibody therapy post-exposure.

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Precise immunoglobulins retrieved from equine serum against EBOV were found safe and effective as prophylactic therapy in non-allergic patients By repeated immunization of mice with glycoproteins of filovirus, generation of pan-EBOV-specific as well as pan-filovirus mAbs have been obtained. The components of ZMapp are mAbs chimeric , viz. The mechanism of action of mAbs is that they identify the inter-protomer epitope of the GP fusion loop, which is essential for viral membrane fusion, and also neutralize the entry of virus In a study by Duehr et al.

Duehr et al. So, it can be used to replace one of the components of ZMapp, thereby increasing the range of protection against SUDV, ultimately leading to generation of cross-protective mAbs cocktail The mAb KZ52 protected guinea pigs from lethal Zaire ebolavirus challenge; however, when an experiment was carried out in rhesus macaques, the antibody failed to protect animals prophylactically and did not inhibit viremia KZ52 is directed to bind a conformational non-glycosylated epitope at base of GP and a total 23 residues of GP residues remain in contact with antibody.

Out of 23, 15 are contacted through van der Waals interactions and remaining 8 through direct hydrogen bonds KZ52 protective efficacy is due to inhibition of cathepsin mediated cleavage of GP Bispecific Trojan-horse antibodies neutralizing other filoviruses have been found to provide protection in mice from multiple EBOV infection These transbodies were effective in blocking viral assembly and budding within the cells as they bind to several cationic patches in the VP40 C-terminal domain. The transbodies inhibit the function of VP40 by additional mechanisms also; such as binding to N-terminal domain and L-domain peptide WW binding motifs, suggesting the potential of these transbodies as direct acting anti-EBOV agents in future The cell-penetrable small antibody fragments HuscFvs or superantibodies [the term coined by Kohler and Paul ] can cross the membrane of all cells but get accumulated intracellularly only where the target antigen is present.

Thus, disappearance of the superantibodies from the blood circulation does not imply that they are eliminated from the body. These mAbs were found to have a neutralizing effect against multiple EBOV species, suggesting the possibility of the use of single mAbs as cross-protecting antibodies The discovery of cross-protective antibodies can aid in the development of therapeutic strategies for treatment of EBOV disease Recognition of the novel epitopes has been performed for Q and Q, wherein these mAbs were found protecting mice against EBOV A therapeutic vaccine based on mAbs has been proposed to sufficiently resolve replication of invasive EBOV, even if administered as a single dose 4 days post-infection Potential limitations of mAb-based therapies include the requirement for high doses and mAb mixtures that are outbreak-specific owing to constant viral evolution.

Furthermore, epitope mutations could reduce efficacy of the therapeutic mAbs used. Hence, these limiting factors need to be taken care of accordingly with mAbs usages. Viral gene expression is dependent on host cell machinery and is critical for virus replication.

Small molecular inhibitors needed for the synthesis of polyamine have been found to block the expression of EBOV gene. However, if eIF5A hypusination is blocked, the gene expression of EBOV is inhibited which subsequently blocks the replication of the virus. Therefore, in-depth understanding of this mechanism at molecular level is essential for developing anti-EBOV drugs It is time taking task to develop a new therapeutic against an infectious agent and till that time new therapy divulged; drug repurposing, i.

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Owing to the lack of approved EBOV therapies, the screening of potentially efficacious drugs revealed that few of the drugs could be repurposed for EBOV treatment Table 2. Amiodarone, dronedarone, and verapamil, which are used for tachycardia, arrhythmias, and high blood pressure or angina, respectively, have been screened for their ability to inhibit the entry of filoviruses into cells and found efficacious in in vitro models The use of statins, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers has also been suggested to attenuate EBOV infection The p38 mitogen-activated protein kinase inhibitor SB was shown to check virus-mediated cytokine storm, as studied in monocyte-derived DC of humans Estrogen re-uptake modulators, viz.

To overcome this, combination therapy is suggested while using such drugs Brincidofovir, a cidofovir analog conjugated with a lipid, can prevent EBOV replication; however, its exact efficacy in an in vivo model needs to be determined Emetine, an anti-protozoal agent, and its desmethyl analog cephaeline have potently inhibited EBOV replication and cephaeline is well tolerated in patients than emetine In EBOV infection, overexpression of the procoagulant tissue factor in monocytes and macrophages and participation of endothelial cells leads to an imbalance in coagulation.

The use of recombinant nematode anticoagulant protein c2, an inhibitor of tissue factor-mediated blood coagulation, was found to improve survival of macaques from Ebola hemorrhagic fever, and hence suggested to act as a good treatment module targeting the disease development There are conflicting reports on the therapeutic effects of chloroquine in mouse, hamster, and guinea pig models of EVD.

Chloroquine was found to inhibit virus replication in in vitro studies but failed to protect against EBOV infection and disease development in mice, hamsters, and guinea pigs , Esomeprazole and omeprazole were also found to inhibit viral entry during in vitro studies but higher concentrations of these drugs may be required when to be used in vivo During the EBOV outbreak in Liberia in , a reduction in fever cases was observed following mass administration of malaria chemoprevention drugs Because of its competitive anti-heparin potential and interference with viral replication and entry into the cell, the anti-trypanosomal agent, Suramin Germanin or Bayer has been proposed to treat EVD A pyrazine carboxamide derivative namely Favipiravir an anti-flu medicine , which was used earlier as an inhibitor of influenza virus replication, has been found useful in both therapy and prophylaxis during EBOV epidemic in West Africa — Favipiravir and the pyrazine carboxamide derivative T showed positive results in treating patients with medium to high viremias, although these drugs were not found to be effective with very high viremias, but revealed acceptable results during EBOV infection in mouse , , Colchicine, a microtubule modulator primarily used for gout, has also been found to show anti-EBOV activity , Drugs like enfuvirtide, vancomycin, bleomycin, octreotide, lanreotide, somatostatin, and ubidecarenone CoQ10 have shown higher activity against EBOV Recently, virtual screening of several thousands of repurposing drugs from Drug Bank has been performed and ibuprofen was selected by realizing its possible inhibitory effect on EBOV infection.

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  7. The drug has been found to show detectable antiviral effect in cell culture and can thus be used as a very useful molecular template for anti-Ebola viral drug development GS developed by Gilead Sciences falls under this category. Interestingly, clinical trials have been conducted and it has been found that the drug is effective in clearing virus from semen , It is also important to note that in NHPs, this compound can provide protection post-exposure Interferons act as potent inhibitors of EBOV as has been proved through in vitro studies conducted involving various types of cells.

    Even though there is increased therapeutic usage of IFNs, but certain side effects are also associated with such treatment, viz. Moreover, the occurrence of malaria additionally should be ruled out before initiating IFN therapy RNAi and advanced antisense therapies have been reported to provide post-exposure protection against lethal filovirus infections In NHPs, it efficiently provided post-exposure protection , Although the results were promising, clinicians did not use much TKM-Ebola as it could lead to lethal overproduction of cytokines a dangerous EBOV-induced inflammatory response Although, the infusion of TKM at a dosage of 0.

    LNP encapsulation is also an effective drug delivery system , This strategy of targeting viral entry could pave way for the development of an anti-EBOV therapeutic agent. Figure 2. Different therapeutic agents and drugs available for the treatment of Ebola virus disease EVD.

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    Some agents block the viral entry, some block the RNA polymerase, while some inhibit gene expression. It helps in evaluating the in vivo anti-EBOV agents, viz. The system appears suitable in studying the process of viral entry also CLR01 interacts with the lipids in the viral envelop but not with the cellular membrane, thereby it is having very less effect on viability of cells This small molecule has earlier been shown to possess antiviral activity against HIV-1 and herpes viruses.

    Such broad-spectrum antiviral agents need to be further explored to develop an effective drug against EBOV. Currently, priority is being given toward investigating various proteins in the host system and viral targets druggable Further research works need to be strengthened to identify potent viral or host targets that can be exploited to treat EVD or inhibit EBOV. With advances in bioinformatics tools, it is now possible to identify the active sites of the viral targets which can be utilized as a critical step toward designing and discovering anti-EBOV drugs The involvement of computational tools has widened our approach toward designing drugs target based widely.

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    Computational approaches can also countervail the endemic burdens in development of drugs traditionally , Large libraries can now be effectively screened, ultimately stimulating research activities toward identifying potent anti-EBOV drugs. The EBOV outbreak has been marked as the most widespread lethal viral hemorrhagic attack and prompted a hasty leap in the researches for developing effective vaccines and therapies to counter it. In recent years, several therapies have emerged to tackle lethal EBOV infections.

    However, the shortage of ZMapp supply warrants the evaluation and development of new mAbs. Various drugs have been repurposed to treat potentially lethal disease like EVD. There is a long list of repurposed compounds that have been evaluated as inhibitors of EBOV, including microtubule inhibitors, estrogen receptor and reuptake modulators, kinase inhibitors, histamine antagonists, and ion channel blockers. In-depth studies are still required to understand the pathogenesis and the role of different EBOV peptides, proteins, and antigens and host—virus interactions in EVD.

    Although the development of vaccines against EBOV began in , there is still no effective vaccine available to prevent this deadly disease. Hence, the hunt for an effective vaccine is still on. Because five EBOV species have been reported, a polyvalent vaccine having immunogenic determinants such as GP from each of species would provide broader immunity; indeed, in nonhuman primate experimental studies with a DNA vaccine, this is commonly true. The best first-generation vaccine candidates for EBOV are rVSV and ChAd3, as reflected by their application in providing long duration protection during sporadic outbreaks.

    Various combinations of antigens from different species of EBOV may be explored to achieve higher protective immune response. Due to absence of preexisting immunity to VSV, it eliminates several drawbacks and safety concerns associated Ad5-based vaccine. Also, it has show long-term protection in several NHP models, it is an ideal vaccine platform to be used at time of outbreak. In addition, mAbs with broad cross-reactivity that will neutralize all five species of EBOV are required to be developed and evaluated for prophylactic and therapeutic uses. Furthermore, effective antibodies may be engineered for homogeneity with human antibodies.

    In the era of genomics, a computational approach may also be employed to screen large numbers of inhibitory molecules to safeguard human health. There is always scope for future investigations on the basis of clinical studies that are designed well and statistically supported. Maximum use of supportive therapy MUST should be introduced for studying the effects of new therapeutics.

    The side effects of newer drugs can also be revealed very efficiently by MUST and for this more resources are needed for the Ebola clinics. Though several drugs have been evaluated and vaccines are in development; however, more research is required to develop potent therapeutic and prophylactic agents against EBOV.

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    Apart from these advances, adaptation of appropriate preventive measures and strict biosecurity principles are essential to stop the EBOV outbreaks, limit the spread of virus, and address its public health significance. All the authors substantially contributed to the conception, design, analysis and interpretation of data, checking and approving final version of the manuscript, and agreed to be accountable for its contents. RK designed tables. KK designed the figures. All authors declare that there exist no commercial or financial relationships that could in any way lead to a potential conflict of interest.

    This compilation is a review article written, analyzed and designed by its authors, and required no substantial funding to be stated. What you need to know about the Ebola virus. J Adv Pract Oncol 5 6 —3. PubMed Abstract Google Scholar. Ebola from emergence to epidemic: the virus and the disease, global preparedness and perspectives. J Infect Dev Ctries — Vet Q 37 1 — Human Ebola outbreak resulting from direct exposure to fruit bats in Luebo, Democratic Republic of Congo.

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    Descriptive analysis of Ebola virus proteins. Virology — Distribution of hydrophobic, residues is crucial for the fusogenic properties of the Ebola virus GP2 fusion peptide. J Virol —6. Filovirus RefSeq entries: evaluation and selection of filovirus type variants, type sequences, and names. Viruses 6 9 — Microbes Infect — A perspective on the development of plant-made vaccines in the fight against Ebola virus. Front Immunol Persistence of Ebola virus in ocular fluid during convalescence.

    Persistence of Ebola virus in ocular fluid during. N Engl J Med 25 —7. Ebola virus persistence in semen of male survivors. Clin Infect Dis 62 12 —5. Ebola viral disease and pregnancy. Obstet Med 8 3 — Evidence of Ebola virus replication and high concentration in semen of a patient during recovery. Clin Infect Dis 65 8 —3. Molecular mechanisms of Ebola virus pathogenesis: focus on cell death. Cell Death Differ —9.

    Babalola MO. Afr J Infect Dis 10 2 — Small animal models for evaluating filovirus countermeasures. ACS Infect Dis The emergence of antibody therapies for Ebola. Hum Antibodies 23 3—4 — Monoclonal antibodies for the treatment of Ebola virus disease. Expert Opin Investig Drugs 25 11 — The ongoing evolution of antibody-based treatments for Ebola virus infection. Immunotherapy 9 5 — Wu W, Liu S. The drug targets and antiviral molecules for treatment of Ebola virus infection. Curr Top Med Chem 17 3 — Protective efficacy of neutralizing monoclonal antibodies in a nonhuman primate model of Ebola hemorrhagic fever.

    PLoS One 7:e Delayed treatment of Ebola virus infection with plant-derived monoclonal antibodies provides protection in rhesus macaques. Successful treatment of Ebola virus-infected cynomolgus macaques with monoclonal antibodies.

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    Sci Transl Med 4 ra Reversion of advanced Ebola virus disease in nonhuman primates with ZMapp. Nature — Ebola vaccine — an urgent international priority. New Engl J Med — Novel surveillance methods for the control of Ebola virus disease.

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    Int Health 9 3 — Joffe S. Evaluating novel therapies during the Ebola epidemic. JAMA — Plant Cell Rep 36 2 — Sharmin R, Islam AB. BMC Bioinformatics 15 — In-silico based vaccine design against Ebola virus glycoprotein. Adv Appl Bioinform Chem — Recent advances in vaccine development against Ebola threat as bioweapon. Virus disease 28 3 —6. Medaglini D, Siegrist CA. Curr Opin Virol — Molecular evidence of sexual transmission of Ebola virus.

    N Engl J Med 25 — Persistence and clearance of Ebola virus RNA from seminal fluid of Ebola virus disease survivors: a longitudinal analysis and modelling study. Lancet Glob Health 5 1 :e80—8. The Ebola Vaccine Team B: a model for promoting the rapid development of medical countermeasures for emerging infectious disease threats. Lancet Infect Dis e1—9. Highly conserved regions in Ebola virus RNA dependent RNA polymerase may be act as a universal novel peptide vaccine target: a computational approach.

    In silico Pharmacol 3 1 Yasmin T, Nabi AH. B and T cell epitope-based peptides predicted from evolutionarily conserved and whole protein sequences of Ebola virus as vaccine targets. Scand J Immunol 83 5 — Ebolavirus glycoprotein Fc fusion protein protects guinea pigs against lethal challenge.

    PLoS One 11 9 :e Containing Ebola at the source with ring vaccination. The secret life of viral entry glycoproteins: moonlighting in immune evasion. PLoS Pathog 9 5 :e Development of a liquid chromatography high resolution mass spectrometry method for the quantitation of viral envelope glycoprotein in Ebola virus-like particle vaccine preparations. Clin Proteomics 13 1 The final oral Ebola vaccine trial on captive Chimpanzees. Sci Rep Modified mRNA-based vaccines elicit robust immune responses and protect guinea pigs from Ebola virus disease.

    J Infect Dis 3 —5. A review of phase I trials of Ebola virus vaccines: what can we learn from the race to develop novel vaccines? Phil Trans R Soc B Considerations for use of Ebola vaccine during an emergency response. Vaccine Inactivated or live-attenuated bivalent vaccines that confer protection against rabies and Ebola viruses. J Virol 85 20 — Inactivated vaccine for Ebola virus efficacious in guineapig model. Brabec, Fei Huang, Yong Cao. Nature Communications , 10 1 DOI: Rapid solvo-microwave annealing for optimizing ordered nanostructures and crystallization of regioregular polythiophene-based block copolymers.

    Polymer Chemistry , 10 36 , DOI: Pair your accounts. Your Mendeley pairing has expired. Please reconnect. This website uses cookies to improve your user experience. By continuing to use the site, you are accepting our use of cookies. Read the ACS privacy policy. Edited by Theophanides Theophile.

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