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1.
Placenta ; 115: 70-77, 2021 11.
Article in English | MEDLINE | ID: covidwho-1433733

ABSTRACT

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/drug therapy , 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
2.
Int J Mol Sci ; 22(3)2021 Jan 26.
Article in English | MEDLINE | ID: covidwho-1389389

ABSTRACT

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/drug therapy , 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
3.
Molecules ; 26(13)2021 Jun 22.
Article in English | MEDLINE | ID: covidwho-1304687

ABSTRACT

Discovery of compound 1 as a Zika virus (ZIKV) inhibitor has prompted us to investigate its 7H-pyrrolo[2,3-d]pyrimidine scaffold, revealing structural features that elicit antiviral activity. Furthermore, we have demonstrated that 9H-purine or 1H-pyrazolo[3,4-d]pyrimidine can serve as an alternative core structure. Overall, we have identified 4,7-disubstituted 7H-pyrrolo[2,3-d]pyrimidines and their analogs including compounds 1, 8 and 11 as promising antiviral agents against flaviviruses ZIKV and dengue virus (DENV). While the molecular target of these compounds is yet to be elucidated, 4,7-disubstituted 7H-pyrrolo[2,3-d]pyrimidines and their analogs are new chemotypes in the design of small molecules against flaviviruses, an important group of human pathogens.


Subject(s)
Antiviral Agents , Pyrimidines , Virus Replication/drug effects , Zika Virus Infection/drug therapy , Zika Virus/physiology , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Cell Line, Tumor , Humans , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Pyrimidines/pharmacology , Zika Virus Infection/metabolism , Zika Virus Infection/pathology
4.
Sci Rep ; 11(1): 11982, 2021 06 07.
Article in English | MEDLINE | ID: covidwho-1260953

ABSTRACT

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 therapy , 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 therapy
5.
Viruses ; 13(4)2021 04 13.
Article in English | MEDLINE | ID: covidwho-1187060

ABSTRACT

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 , COVID-19/drug therapy , 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
6.
Int J Mol Sci ; 22(3)2021 Jan 26.
Article in English | MEDLINE | ID: covidwho-1050617

ABSTRACT

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/drug therapy , 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
7.
Mater Sci Eng C Mater Biol Appl ; 112: 110924, 2020 Jul.
Article in English | MEDLINE | ID: covidwho-1017020

ABSTRACT

Research on highly effective antiviral drugs is essential for preventing the spread of infections and reducing losses. Recently, many functional nanoparticles have been shown to possess remarkable antiviral ability, such as quantum dots, gold and silver nanoparticles, nanoclusters, carbon dots, graphene oxide, silicon materials, polymers and dendrimers. Despite their difference in antiviral mechanism and inhibition efficacy, these functional nanoparticles-based structures have unique features as potential antiviral candidates. In this topical review, we highlight the antiviral efficacy and mechanism of these nanoparticles. Specifically, we introduce various methods for analyzing the viricidal activity of functional nanoparticles and the latest advances in antiviral functional nanoparticles. Furthermore, we systematically describe the advantages and disadvantages of these functional nanoparticles in viricidal applications. Finally, we discuss the challenges and prospects of antiviral nanostructures. This topic review covers 132 papers and will enrich our knowledge about the antiviral efficacy and mechanism of various functional nanoparticles.


Subject(s)
Antiviral Agents/chemistry , Nanoparticles/chemistry , Animals , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , DNA Viruses/drug effects , DNA Viruses/physiology , Graphite/chemistry , Metal Nanoparticles/chemistry , Metal Nanoparticles/toxicity , Nanoparticles/therapeutic use , Nanoparticles/toxicity , Polymers/chemistry , Quantum Dots/chemistry , Quantum Dots/therapeutic use , Quantum Dots/toxicity , Zika Virus/drug effects , Zika Virus Infection/drug therapy , Zika Virus Infection/veterinary
8.
Sci Total Environ ; 759: 143539, 2021 Mar 10.
Article in English | MEDLINE | ID: covidwho-912621

ABSTRACT

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/epidemiology
9.
Biochemistry ; 60(13): 999-1018, 2021 04 06.
Article in English | MEDLINE | ID: covidwho-889110

ABSTRACT

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/drug therapy , 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
10.
Curr Med Chem ; 28(15): 2887-2942, 2021.
Article in English | MEDLINE | ID: covidwho-713257

ABSTRACT

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 therapy
11.
Virology ; 546: 88-97, 2020 07.
Article in English | MEDLINE | ID: covidwho-71808

ABSTRACT

The emergence and re-emergence of Zika virus (ZIKV), is a cause for international concern. These highly pathogenic arboviruses represent a serious health burden in tropical and subtropical areas worldwide. Despite these burdens, antiviral therapies do not exist, and inhibitors of ZIKV are therefore urgently needed. To elucidate the anti-ZIKV effect of lycorine, we used reverse transcription-quantitative real-time PCR (qRT-PCR), immunofluorescence, Westernwestern blot, and plaque forming assay to analyse viral RNA (vRNA), viral protein, progeny virus counts, and validated inhibitors in vitro using a variety of cell lines. Additionally, we found that lycorine acts post-infection according to time-of-addition assay, and inhibits RdRp activity. Lycorine protected AG6 mice against ZIKV-induced lethality by decreasing the viral load in the blood. Due to its potency and ability to target ZIKV infection in vivo and in vitro, lycorine might offer promising therapeutic possibilities for combatting ZIKV infections in the future.


Subject(s)
Amaryllidaceae Alkaloids/administration & dosage , Antiviral Agents/administration & dosage , Phenanthridines/administration & dosage , Zika Virus Infection/drug therapy , Zika Virus/drug effects , Amaryllidaceae Alkaloids/chemistry , Animals , Antiviral Agents/chemistry , Female , Humans , Male , Mice , Molecular Docking Simulation , Phenanthridines/chemistry , Virus Replication/drug effects , Zika Virus/genetics , Zika Virus/physiology , Zika Virus Infection/mortality , Zika Virus Infection/virology
12.
Drug Discov Today ; 25(5): 928-941, 2020 05.
Article in English | MEDLINE | ID: covidwho-72302

ABSTRACT

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.


Subject(s)
Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Drug Discovery , Pneumonia, Viral/drug therapy , Angiotensin-Converting Enzyme 2 , Animals , Betacoronavirus/metabolism , COVID-19 , Chlorocebus aethiops , Computer Simulation , Drug Repositioning , Hemorrhagic Fever, Ebola/drug therapy , Humans , In Vitro Techniques , Middle East Respiratory Syndrome Coronavirus , Molecular Docking Simulation , Pandemics , Peptidyl-Dipeptidase A/metabolism , SARS Virus , SARS-CoV-2 , Severe Acute Respiratory Syndrome/drug therapy , Spike Glycoprotein, Coronavirus/metabolism , Vero Cells , Zika Virus Infection/drug therapy
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