ABSTRACT
Chikungunya virus (CHIKV) and Zika virus (ZIKV) are important disease-causing agents worldwide. Currently, there are no antiviral drugs or vaccines approved to treat these viruses. However, peptides have shown great potential for new drug development. A recent study described (p-BthTX-I)2K [(KKYRYHLKPF)2K], a peptide derived from the Bothropstoxin-I toxin in the venom of the Bothrops jararacussu snake, showed antiviral activity against SARS-CoV-2. In this study, we assessed the activity of this peptide against CHIKV and ZIKV and its antiviral action in the different stages of the viral replication cycle in vitro. We observed that (p-BthTX-I)2K impaired CHIKV infection by interfering with the early steps of the viral replication cycle, reducing CHIKV entry into BHK-21 cells specifically by reducing both the attachment and internalization steps. (p-BthTX-I)2K also inhibited the ZIKV replicative cycle in Vero cells. The peptide protected the cells against ZIKV infection and decreased the levels of the viral RNA and the NS3 protein of this virus at viral post-entry steps. In conclusion, this study highlights the potential of the (p-BthTX-I)2K peptide to be a novel broad-spectrum antiviral candidate that targets different steps of the replication cycle of both CHIKV and ZIKV.
Subject(s)
COVID-19 , Chikungunya Fever , Chikungunya virus , Viruses , Zika Virus Infection , Zika Virus , Animals , Chlorocebus aethiops , Humans , Zika Virus Infection/drug therapy , Zika Virus/genetics , Vero Cells , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Virus Replication , SARS-CoV-2 , Chikungunya virus/genetics , Peptides/pharmacology , Peptides/therapeutic useABSTRACT
The flavivirus genus contains several clinically important pathogens that account for tremendous global suffering. Primarily transmitted by mosquitos or ticks, these viruses can cause severe and potentially fatal diseases ranging from hemorrhagic fevers to encephalitis. The extensive global burden is predominantly caused by six flaviviruses: dengue, Zika, West Nile, yellow fever, Japanese encephalitis and tick-borne encephalitis. Several vaccines have been developed, and many more are currently being tested in clinical trials. However, flavivirus vaccine development is still confronted with many shortcomings and challenges. With the use of the existing literature, we have studied these hurdles as well as the signs of progress made in flavivirus vaccinology in the context of future development strategies. Moreover, all current licensed and phase-trial flavivirus vaccines have been gathered and discussed based on their vaccine type. Furthermore, potentially relevant vaccine types without any candidates in clinical testing are explored in this review as well. Over the past decades, several modern vaccine types have expanded the field of vaccinology, potentially providing alternative solutions for flavivirus vaccines. These vaccine types offer different development strategies as opposed to traditional vaccines. The included vaccine types were live-attenuated, inactivated, subunit, VLPs, viral vector-based, epitope-based, DNA and mRNA vaccines. Each vaccine type offers different advantages, some more suitable for flaviviruses than others. Additional studies are needed to overcome the barriers currently faced by flavivirus vaccine development, but many potential solutions are currently being explored.
Subject(s)
Flavivirus Infections , Flavivirus , Viral Vaccines , Yellow Fever , Zika Virus Infection , Zika Virus , Animals , Humans , Flavivirus/genetics , Mosquito Vectors , Yellow Fever/prevention & control , Zika Virus Infection/drug therapyABSTRACT
The recent COVID-19 crisis has highlighted the importance of RNA-based viruses. The most prominent members of this group are SARS-CoV-2 (coronavirus), HIV (human immunodeficiency virus), EBOV (Ebola virus), DENV (dengue virus), HCV (hepatitis C virus), ZIKV (Zika virus), CHIKV (chikungunya virus), and influenza A virus. With the exception of retroviruses which produce reverse transcriptase, the majority of RNA viruses encode RNA-dependent RNA polymerases which do not include molecular proofreading tools, underlying the high mutation capacity of these viruses as they multiply in the host cells. Together with their ability to manipulate the immune system of the host in different ways, their high mutation frequency poses a challenge to develop effective and durable vaccination and/or treatments. Consequently, the use of antiviral targeting agents, while an important part of the therapeutic strategy against infection, may lead to the selection of drug-resistant variants. The crucial role of the host cell replicative and processing machinery is essential for the replicative cycle of the viruses and has driven attention to the potential use of drugs directed to the host machinery as therapeutic alternatives to treat viral infections. In this review, we discuss small molecules with antiviral effects that target cellular factors in different steps of the infectious cycle of many RNA viruses. We emphasize the repurposing of FDA-approved drugs with broad-spectrum antiviral activity. Finally, we postulate that the ferruginol analog (18-(phthalimide-2-yl) ferruginol) is a potential host-targeted antiviral.
Subject(s)
COVID-19 , RNA Viruses , Viruses , Zika Virus Infection , Zika Virus , Humans , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Zika Virus Infection/drug therapy , Virus Replication , SARS-CoV-2 , RNAABSTRACT
Positive-strand RNA viruses have been the cause of several recent outbreaks and epidemics, including the Zika virus epidemic in 2015, the SARS outbreak in 2003, and the ongoing SARS-CoV-2 pandemic. On June 18-22, 2022, researchers focusing on positive-strand RNA viruses met for the Keystone Symposium "Positive-Strand RNA Viruses" to share the latest research in molecular and cell biology, virology, immunology, vaccinology, and antiviral drug development. This report presents concise summaries of the scientific discussions at the symposium.
Subject(s)
COVID-19 , Zika Virus Infection , Zika Virus , Humans , SARS-CoV-2 , Positive-Strand RNA Viruses , Antiviral Agents/therapeutic use , Pandemics , Zika Virus Infection/epidemiology , Zika Virus Infection/prevention & control , Zika Virus Infection/drug therapyABSTRACT
Viral infection almost invariably causes metabolic changes in the infected cell and several types of host cells that respond to the infection. Among metabolic changes, the most prominent is the upregulated glycolysis process as the main pathway of glucose utilization. Glycolysis activation is a common mechanism of cell adaptation to several viral infections, including noroviruses, rhinoviruses, influenza virus, Zika virus, cytomegalovirus, coronaviruses and others. Such metabolic changes provide potential targets for therapeutic approaches that could reduce the impact of infection. Glycolysis inhibitors, especially 2-deoxy-D-glucose (2-DG), have been intensively studied as antiviral agents. However, 2-DG's poor pharmacokinetic properties limit its wide clinical application. Herein, we discuss the potential of 2-DG and its novel analogs as potent promising antiviral drugs with special emphasis on targeted intracellular processes.
Subject(s)
COVID-19 , Zika Virus Infection , Zika Virus , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Deoxyglucose/pharmacology , Glucose , Glycolysis , Humans , Mannose , SARS-CoV-2 , Zika Virus Infection/drug therapyABSTRACT
The COVID-19 pandemic has exemplified that rigorous evaluation in large animal models is key for translation from promising in vitro results to successful clinical implementation. Among the drugs that have been largely tested in clinical trials but failed so far to bring clear evidence of clinical efficacy is favipiravir, a nucleoside analogue with large spectrum activity against several RNA viruses in vitro and in small animal models. Here, we evaluate the antiviral activity of favipiravir against Zika or SARS-CoV-2 virus in cynomolgus macaques. In both models, high doses of favipiravir are initiated before infection and viral kinetics are evaluated during 7 to 15 days after infection. Favipiravir leads to a statistically significant reduction in plasma Zika viral load compared to untreated animals. However, favipiravir has no effects on SARS-CoV-2 viral kinetics, and 4 treated animals have to be euthanized due to rapid clinical deterioration, suggesting a potential role of favipiravir in disease worsening in SARS-CoV-2 infected animals. To summarize, favipiravir has an antiviral activity against Zika virus but not against SARS-CoV-2 infection in the cynomolgus macaque model. Our results support the clinical evaluation of favipiravir against Zika virus but they advocate against its use against SARS-CoV-2 infection.
Subject(s)
COVID-19 Drug Treatment , Zika Virus Infection , Zika Virus , Amides , Animals , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Humans , Macaca fascicularis , Pandemics , Primates , Pyrazines , SARS-CoV-2 , Zika Virus Infection/drug therapyABSTRACT
The COVID-19 pandemic marks an inflection point in the perception and treatment of human health. Substantial resources have been reallocated to address the direct medical effects of COVID-19 and to curtail the spread of the virus. Thereby, shortcomings of traditional disinfectants, especially their requirement for regular reapplication and the related complications (e.g., dedicated personnel and short-term activity), have become issues at the forefront of public health concerns. This issue became especially pressing when infection-mitigating supplies dwindled early in the progression of the pandemic. In consideration of the constant threat posed by emerging novel viruses, we report a platform technology for persistent surface disinfection to combat virus transmission through nanomaterial-mediated, localized UV radiation emission. In this work, two formulations of Y2SiO5-based visible-to-UV upconversion nanomaterials were developed using a facile sol-gel-based synthesis. Our formulations have shown substantial antiviral activities (4 × 104 to 0 TCID50 units in 30 min) toward an enveloped, circulating human coronavirus strain (OC43) under simple white light exposure as an analogue to natural light or common indoor lighting. Additionally, we have shown that our two formulations greatly reduce OC43 RNA recovery from surfaces. Antiviral activities were further demonstrated toward a panel of structurally diverse viruses including enveloped viruses, SARS-CoV-2, vaccinia virus, vesicular stomatitis virus, parainfluenza virus, and Zika virus, as well as nonenveloped viruses, rhinovirus, and calicivirus, as evidence of the technology's broad antiviral activity. Remarkably, one formulation completely inactivated 105 infectious units of SARS-CoV-2 in only 45 min. The detailed technology has implications for the design of more potent, long-lived disinfectants and modified/surface-treated personal protective equipment targeting a wide range of viruses.
Subject(s)
COVID-19 , Disinfectants , Viruses , Zika Virus Infection , Zika Virus , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Humans , Pandemics , SARS-CoV-2 , Zika Virus Infection/drug therapyABSTRACT
Zika virus (ZIKV) is a mosquito-borne flavivirus that emerged in the Pacific islands in 2007 and spread to the Americas in 2015. The infection remains asymptomatic in most cases but can be associated with severe neurological disorders. Despite massive efforts, no specific drug or vaccine against ZIKV infection is available to date. Claudins are tight-junction proteins that favor the entry of several flaviviruses, including ZIKV. In this study, we identified two peptides derived from the N-terminal sequences of claudin-7 and claudin-1, named CL7.1 and CL1.1, respectively, that inhibited ZIKV infection in a panel of human cell lines. Using cell-to-cell fusion assays, we demonstrated that these peptides blocked the ZIKV E-mediated membrane fusion. A comparison of the antiviral efficacy of CL1.1 and CL7.1 pointed to the importance of the peptide amphipathicity. Electron microscopic analysis revealed that CL1.1 altered the ultrastructure of the viral particles likely by binding the virus lipid envelope. However, amphipathicity could not fully explain the antiviral activity of CL1.1. In silico docking simulations suggested that CL1.1 may also interact with the E protein, near its stem region. Overall, our data suggested that claudin-derived peptides inhibition may be linked to simultaneous interaction with the E protein and the viral lipid envelope. Finally, we found that CL1.1 also blocked infection by yellow fever and Japanese encephalitis viruses but not by HIV-1 or SARS-CoV-2. Our results provide a basis for the future development of therapeutics against a wide range of endemic and emerging flaviviruses. IMPORTANCE Zika virus (ZIKV) is a flavivirus transmitted by mosquito bites that have spread to the Pacific Islands and the Americas over the past decade. The infection remains asymptomatic in most cases but can cause severe neurological disorders. ZIKV is a major public health threat in areas of endemicity, and there is currently no specific antiviral drug or vaccine available. We identified two antiviral peptides deriving from the N-terminal sequences of claudin-7 and claudin-1 with the latter being the most effective. These peptides block the envelope-mediated membrane fusion. Our data suggested that the inhibition was likely achieved by simultaneously interacting with the viral lipid envelope and the E protein. The peptides also inhibited other flaviviruses. These results could provide the basis for the development of therapies that might target a wide array of flaviviruses from current epidemics and possibly future emergences.
Subject(s)
Claudins , Membrane Fusion , Zika Virus Infection , Zika Virus , Humans , Antiviral Agents/pharmacology , Claudin-1 , Lipids , Peptides/pharmacology , Zika Virus Infection/drug therapyABSTRACT
There is a pressing need for host-directed therapeutics that elicit broad-spectrum antiviral activities to potentially address current and future viral pandemics. Apratoxin S4 (Apra S4) is a potent Sec61 inhibitor that prevents cotranslational translocation of secretory proteins into the endoplasmic reticulum (ER), leading to anticancer and antiangiogenic activity both in vitro and in vivo. Since Sec61 has been shown to be an essential host factor for viral proteostasis, we tested Apra S4 in cellular models of viral infection, including SARS-CoV-2, influenza A virus, and flaviviruses (Zika, West Nile, and Dengue virus). Apra S4 inhibited viral replication in a concentration-dependent manner and had high potency particularly against SARS-CoV-2 and influenza A virus, with subnanomolar activity in human cells. Characterization studies focused on SARS-CoV-2 revealed that Apra S4 impacted a post-entry stage of the viral life-cycle. Transmission electron microscopy revealed that Apra S4 blocked formation of stacked double-membrane vesicles, the sites of viral replication. Apra S4 reduced dsRNA formation and prevented viral protein production and trafficking of secretory proteins, especially the spike protein. Given the potent and broad-spectrum activity of Apra S4, further preclinical evaluation of Apra S4 and other Sec61 inhibitors as antivirals is warranted.
Subject(s)
COVID-19 Drug Treatment , Influenza A virus , Zika Virus Infection , Zika Virus , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Depsipeptides , Humans , Pandemics , SARS-CoV-2 , Zika Virus Infection/drug therapyABSTRACT
Viral infection is clinically common and some viral diseases, such as the ongoing global outbreak of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), have high morbidity and mortality. However, most viral infections are currently lacking in specific therapeutic agents and effective prophylactic vaccines, due to inadequate response, increased rate of drug resistance and severe adverse side effects. Therefore, it is urgent to find new specific therapeutic targets for antiviral defense among which "peptide-based therapeutics" is an emerging field. Peptides may be promising antiviral drugs because of their high efficacy and low toxic side effects. Vasoactive intestinal peptide (VIP) is a prospective antiviral peptide. Since its successful isolation in 1970, VIP has been reported to be involved in infections of SARS-CoV-2, human immune deficiency virus (HIV), vesicular stomatitis virus (VSV), respiratory syncytial virus (RSV), Zika virus (ZIKV) and cytomegalovirus (CMV). Additionally, given that viral attacks sometimes cause severe complications due to overaction of inflammatory and immune responses, the potent anti-inflammatory and immunoregulator properties of VIP facilitate it to be a powerful and promising candidate. This review summarizes the role and mechanisms of VIP in all reported viral infections and suggests its clinical potential as an antiviral therapeutic target.
Subject(s)
COVID-19 Drug Treatment , Zika Virus Infection , Zika Virus , Antiviral Agents/therapeutic use , Humans , Prospective Studies , SARS-CoV-2 , Vasoactive Intestinal Peptide/therapeutic use , Zika Virus Infection/drug therapyABSTRACT
Species differences are among the main reasons for the high failure rate of preclinical studies. A better awareness and understanding of these differences might help to improve the outcome of preclinical research. In reproduction, the placenta is the central organ regulating fetal exposure to a substance circulating in the maternal organism. Exact information about placental transfer can help to better estimate the toxic potential of a substance. From an evolutionary point of view, the chorioallantoic placenta is the organ with the highest anatomical diversity among species. Moreover, frequently used animal models in reproduction belong to rodents and lagomorphs, two groups that are characterized by the generation of an additional type of placenta, which is crucial for fetal development, but absent from humans: the inverted yolk sac placenta. Taken together, the translatability of placental transfer studies from laboratory animals to humans is challenging, which is supported by the fact that numerous species-dependent toxic effects are described in literature. Thus, reliable human-relevant data are frequently lacking and the toxic potential of chemicals and pharmaceuticals for humans can hardly be estimated, often resulting in recommendations that medical treatments or exposure to chemicals should be avoided for safety reasons. Although species differences of placental anatomy have been described frequently and the need for human-relevant research models has been emphasized, analyses of substances with species-dependent placental transfer have been performed only sporadically. Here, we present examples for species-specific placental transfer, including that of nanoparticles and pharmaceuticals, and discuss potential underlying mechanisms. With respect to the COVID 19-pandemic it might be of interest that some antiviral drugs are reported to feature species-specific placental transfer. Further, differences in placental structure and antibody transfer may affect placental transfer of ZIKA virus.
Subject(s)
Maternal-Fetal Exchange/physiology , Placenta/metabolism , Animals , Antiviral Agents/pharmacokinetics , Biological Transport/physiology , COVID-19/transmission , COVID-19/virology , Female , Humans , Infectious Disease Transmission, Vertical , Maternal-Fetal Exchange/drug effects , Placenta/drug effects , Pregnancy , Pregnancy Complications, Infectious/drug therapy , Pregnancy Complications, Infectious/metabolism , Pregnancy Complications, Infectious/virology , SARS-CoV-2/metabolism , Species Specificity , Yolk Sac/metabolism , Yolk Sac/physiology , Zika Virus/metabolism , Zika Virus Infection/drug therapy , Zika Virus Infection/transmission , COVID-19 Drug TreatmentABSTRACT
A high-throughput drug screen identifies potentially promising therapeutics for clinical trials. However, limitations that persist in current disease modeling with limited physiological relevancy of human patients skew drug responses, hamper translation of clinical efficacy, and contribute to high clinical attritions. The emergence of induced pluripotent stem cell (iPSC) technology revolutionizes the paradigm of drug discovery. In particular, iPSC-based three-dimensional (3D) tissue engineering that appears as a promising vehicle of in vitro disease modeling provides more sophisticated tissue architectures and micro-environmental cues than a traditional two-dimensional (2D) culture. Here we discuss 3D based organoids/spheroids that construct the advanced modeling with evolved structural complexity, which propels drug discovery by exhibiting more human specific and diverse pathologies that are not perceived in 2D or animal models. We will then focus on various central nerve system (CNS) disease modeling using human iPSCs, leading to uncovering disease pathogenesis that guides the development of therapeutic strategies. Finally, we will address new opportunities of iPSC-assisted drug discovery with multi-disciplinary approaches from bioengineering to Omics technology. Despite technological challenges, iPSC-derived cytoarchitectures through interactions of diverse cell types mimic patients' CNS and serve as a platform for therapeutic development and personalized precision medicine.
Subject(s)
Central Nervous System Diseases/drug therapy , Drug Discovery/methods , Induced Pluripotent Stem Cells/cytology , Induced Pluripotent Stem Cells/drug effects , Tissue Engineering/methods , Animals , COVID-19/pathology , Central Nervous System Diseases/pathology , Drug Discovery/instrumentation , Drug Evaluation, Preclinical/instrumentation , Drug Evaluation, Preclinical/methods , Humans , Induced Pluripotent Stem Cells/pathology , Lab-On-A-Chip Devices , Organoids/cytology , Organoids/drug effects , Organoids/pathology , Tissue Engineering/instrumentation , Zika Virus Infection/drug therapy , Zika Virus Infection/pathology , COVID-19 Drug TreatmentABSTRACT
The smallest of all the pathogens, viruses, have continuously been the foremost strange microorganisms. Viral infections can cause extreme sicknesses as evidenced by the HIV/AIDS widespread or the later Ebola or Zika episodes. Apprehensive framework distortions are also regularly observed as consequences of numerous viral infections. Besides, numerous viral infections are of oncoviruses, which can trigger different types of cancer. Nearly every year, a modern infectious species emerges, debilitating the world population with an annihilating episode. Subsequently, there is a need to create antivirals to combat such rising infections. From the discovery of the antiviral drug Idoxuridine in 1962 to the revelation of Baloxavir marboxil (Xofluza) that was approved by the FDA in 2018, the whole process and criteria of creating antivirals have changed significantly. In this article, different auxiliary science strategies are described that can serve as a referral for therapeutic innovation.
Subject(s)
Virus Diseases , Viruses , Zika Virus Infection , Zika Virus , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Humans , Virus Diseases/drug therapy , Zika Virus Infection/drug therapyABSTRACT
In this study we have developed a method based on Flux Balance Analysis to identify human metabolic enzymes which can be targeted for therapeutic intervention against COVID-19. A literature search was carried out in order to identify suitable inhibitors of these enzymes, which were confirmed by docking calculations. In total, 10 targets and 12 bioactive molecules have been predicted. Among the most promising molecules we identified Triacsin C, which inhibits ACSL3, and which has been shown to be very effective against different viruses, including positive-sense single-stranded RNA viruses. Similarly, we also identified the drug Celgosivir, which has been successfully tested in cells infected with different types of viruses such as Dengue, Zika, Hepatitis C and Influenza. Finally, other drugs targeting enzymes of lipid metabolism, carbohydrate metabolism or protein palmitoylation (such as Propylthiouracil, 2-Bromopalmitate, Lipofermata, Tunicamycin, Benzyl Isothiocyanate, Tipifarnib and Lonafarnib) are also proposed.
Subject(s)
Antiviral Agents/pharmacology , COVID-19 Drug Treatment , Molecular Docking Simulation , SARS-CoV-2/drug effects , Virus Replication/drug effects , Dengue Virus/drug effects , Hepacivirus/drug effects , Zika Virus/drug effects , Zika Virus Infection/drug therapyABSTRACT
The emergence or re-emergence of viruses with epidemic and/or pandemic potential, such as Ebola, Zika, Middle East Respiratory Syndrome (MERS-CoV), Severe Acute Respiratory Syndrome Coronavirus 1 and 2 (SARS and SARS-CoV-2) viruses, or new strains of influenza represents significant human health threats due to the absence of available treatments. Vaccines represent a key answer to control these viruses. However, in the case of a public health emergency, vaccine development, safety, and partial efficacy concerns may hinder their prompt deployment. Thus, developing broad-spectrum antiviral molecules for a fast response is essential to face an outbreak crisis as well as for bioweapon countermeasures. So far, broad-spectrum antivirals include two main categories: the family of drugs targeting the host-cell machinery essential for virus infection and replication, and the family of drugs directly targeting viruses. Among the molecules directly targeting viruses, nucleoside analogues form an essential class of broad-spectrum antiviral drugs. In this review, we will discuss the interest for broad-spectrum antiviral strategies and their limitations, with an emphasis on virus-targeted, broad-spectrum, antiviral nucleoside analogues and their mechanisms of action.
Subject(s)
Antiviral Agents/pharmacology , Nucleosides/analogs & derivatives , Nucleosides/pharmacology , Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Amides , Animals , Antiviral Agents/chemistry , Hemorrhagic Fever, Ebola/drug therapy , Humans , Middle East Respiratory Syndrome Coronavirus/drug effects , Mutagenesis , Pyrazines , Ribavirin , SARS-CoV-2 , Virus Replication/drug effects , Zika Virus/drug effects , Zika Virus Infection/drug therapy , COVID-19 Drug TreatmentABSTRACT
In the current scenario, the increasing prevalence of diverse microbial infections as well as emergence and re-emergence of viral epidemics with high morbidity and mortality rates are major public health threat. Despite the persistent production of antiviral drugs and vaccines in the global market, viruses still remain as one of the leading causes of deadly human diseases. Effective control of viral diseases, particularly Zika virus disease, Nipah virus disease, Severe acute respiratory syndrome, Coronavirus disease, Herpes simplex virus infection, Acquired immunodeficiency syndrome, and Ebola virus disease remain promising goal amidst the mutating viral strains. Current trends in the development of antiviral drugs focus solely on testing novel drugs or repurposing drugs against potential targets of the viruses. Compared to synthetic drugs, medicines from natural resources offer less side-effect to humans and are often cost-effective in the productivity approaches. This review intends not only to emphasize on the major viral disease outbreaks in the past few decades and but also explores the potentialities of natural substances as antiviral traits to combat viral pathogens. Here, we spotlighted a comprehensive overview of antiviral components present in varied natural sources, including plants, fungi, and microorganisms in order to identify potent antiviral agents for developing alternative therapy in future.
Subject(s)
Antiviral Agents , Epidemics , Virus Diseases , Zika Virus Infection , Zika Virus , Disease Outbreaks , Humans , Natural Resources , Virus Diseases/epidemiology , Zika Virus Infection/drug therapy , Zika Virus Infection/epidemiologyABSTRACT
Carbohydrate-receptor interactions are often involved in the docking of viruses to host cells, and this docking is a necessary step in the virus life cycle that precedes infection and, ultimately, replication. Despite the conserved structures of the glycans involved in docking, they are still considered "undruggable", meaning these glycans are beyond the scope of conventional pharmacological strategies. Recent advances in the development of synthetic carbohydrate receptors (SCRs), small molecules that bind carbohydrates, could bring carbohydrate-receptor interactions within the purview of druggable targets. Here we discuss the role of carbohydrate-receptor interactions in viral infection, the evolution of SCRs, and recent results demonstrating their ability to prevent viral infections in vitro. Common SCR design strategies based on boronic ester formation, metal chelation, and noncovalent interactions are discussed. The benefits of incorporating the idiosyncrasies of natural glycan-binding proteins-including flexibility, cooperativity, and multivalency-into SCR design to achieve nonglucosidic specificity are shown. These studies into SCR design and binding could lead to new strategies for mitigating the grave threat to human health posed by enveloped viruses, which are heavily glycosylated viroids that are the cause of some of the most pressing and untreatable diseases, including HIV, Dengue, Zika, influenza, and SARS-CoV-2.
Subject(s)
Antiviral Agents/chemistry , Drug Design , Receptors, Artificial/chemistry , Receptors, Virus/metabolism , Small Molecule Libraries/chemistry , Virus Attachment/drug effects , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , COVID-19/metabolism , Carbohydrate Metabolism/drug effects , Chlorocebus aethiops , Humans , Molecular Docking Simulation , Receptors, Artificial/chemical synthesis , Receptors, Virus/antagonists & inhibitors , SARS-CoV-2/drug effects , Small Molecule Libraries/chemical synthesis , Small Molecule Libraries/pharmacology , Vero Cells , Virus Diseases/drug therapy , Virus Diseases/metabolism , Zika Virus/drug effects , Zika Virus Infection/drug therapy , Zika Virus Infection/metabolism , COVID-19 Drug TreatmentABSTRACT
BACKGROUND: Viral diseases are responsible for several deaths around the world. Over the past few years, the world has seen several outbreaks caused by viral diseases that, for a long time, seemed to possess no risk. These are diseases that have been forgotten for a long time and, until nowadays, there are no approved drugs or vaccines, leading the pharmaceutical industry and several research groups to run out of time in the search for new pharmacological treatments or prevention methods. In this context, drug repurposing proves to be a fast and economically viable technique, considering the fact that it uses drugs that have a well-established safety profile. Thus, in this review, we present the main advances in drug repurposing and their benefit for searching new treatments against emerging viral diseases. METHODS: We conducted a search in the bibliographic databases (Science Direct, Bentham Science, PubMed, Springer, ACS Publisher, Wiley, and NIH's COVID-19 Portfolio) using the keywords "drug repurposing", "emerging viral infections" and each of the diseases reported here (CoV; ZIKV; DENV; CHIKV; EBOV and MARV) as an inclusion/exclusion criterion. A subjective analysis was performed regarding the quality of the works for inclusion in this manuscript. Thus, the selected works were those that presented drugs repositioned against the emerging viral diseases presented here by means of computational, high-throughput screening or phenotype-based strategies, with no time limit and of relevant scientific value. RESULTS: 291 papers were selected, 24 of which were CHIKV; 52 for ZIKV; 43 for DENV; 35 for EBOV; 10 for MARV; and 56 for CoV and the rest (72 papers) related to the drugs repurposing and emerging viral diseases. Among CoV-related articles, most were published in 2020 (31 papers), updating the current topic. Besides, between the years 2003 - 2005, 10 articles were created, and from 2011 - 2015, there were 7 articles, portraying the outbreaks that occurred at that time. For ZIKV, similar to CoV, most publications were during the period of outbreaks between the years 2016 - 2017 (23 articles). Similarly, most CHIKV (13 papers) and DENV (14 papers) publications occur at the same time interval. For EBOV (13 papers) and MARV (4 papers), they were between the years 2015 - 2016. Through this review, several drugs were highlighted that can be evolved in vivo and clinical trials as possible used against these pathogens showed that remdesivir represent potential treatments against CoV. Furthermore, ribavirin may also be a potential treatment against CHIKV; sofosbuvir against ZIKV; celgosivir against DENV, and favipiravir against EBOV and MARV, representing new hopes against these pathogens. CONCLUSION: The conclusions of this review manuscript show the potential of the drug repurposing strategy in the discovery of new pharmaceutical products, as from this approach, drugs could be used against emerging viral diseases. Thus, this strategy deserves more attention among research groups and is a promising approach to the discovery of new drugs against emerging viral diseases and also other diseases.
Subject(s)
COVID-19 , Zika Virus Infection , Zika Virus , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Drug Repositioning , Humans , SARS-CoV-2 , Zika Virus Infection/drug therapyABSTRACT
In the past decade we have seen two major Ebola virus outbreaks in Africa, the Zika virus in Brazil and the Americas and the current pandemic of coronavirus disease (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). There is a strong sense of déjà vu because there are still no effective treatments. In the COVID-19 pandemic, despite being a new virus, there are already drugs suggested as active in in vitro assays that are being repurposed in clinical trials. Promising SARS-CoV-2 viral targets and computational approaches are described and discussed. Here, we propose, based on open antiviral drug discovery approaches for previous outbreaks, that there could still be gaps in our approach to drug discovery.