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1.
Infect Dis Poverty ; 10(1): 28, 2021 Mar 16.
Article in English | MEDLINE | ID: covidwho-1135002

ABSTRACT

BACKGROUND: Coronaviruses (CoVs) are distributed worldwide and have various susceptible hosts; CoVs infecting humans are called human coronaviruses (HCoVs). Although HCoV-specific drugs are still lacking, many potent targets for drug discovery are being explored, and many vigorously designed clinical trials are being carried out in an orderly manner. The aim of this review was to gain a comprehensive understanding of the current status of drug development against HCoVs, particularly severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). MAIN TEXT: A scoping review was conducted by electronically searching research studies, reviews, and clinical trials in PubMed and the CNKI. Studies on HCoVs and therapeutic drug discovery published between January 2000 and October 2020 and in English or Chinese were included, and the information was summarized. Of the 3248 studies identified, 159 publication were finally included. Advances in drug development against HCoV, especially SARS-CoV-2, are summarized under three categories: antiviral drugs aimed at inhibiting the HCoV proliferation process, drugs acting on the host's immune system, and drugs derived from plants with potent activity. Furthermore, clinical trials of drugs targeting SARS-CoV-2 are summarized. CONCLUSIONS: During the spread of COVID-19 outbreak, great efforts have been made in therapeutic drug discovery against the virus, although the pharmacological effects and adverse reactions of some drugs under study are still unclear. However, well-designed high-quality studies are needed to further study the effectiveness and safety of these potential drugs so as to provide valid recommendations for better control of the COVID-19 pandemic.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus Infections/virology , Coronavirus/drug effects , Coronavirus/physiology , Drug Discovery , Antiviral Agents/therapeutic use , Biomarkers , /metabolism , Coronavirus/classification , Coronavirus Infections/drug therapy , Coronavirus Infections/metabolism , Drug Development , Drug Discovery/methods , Gene Expression Regulation, Viral , Host-Pathogen Interactions , Humans , Medicine, Traditional , Molecular Targeted Therapy , Virus Replication/drug effects
2.
Peptides ; 139: 170526, 2021 05.
Article in English | MEDLINE | ID: covidwho-1117455

ABSTRACT

The Coronaviridae family comprises large enveloped single-stranded RNA viruses. The known human-infecting coronaviruses; severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), novel SARS-CoV-2, human coronavirus (HCoV)-NL63, HCoV-229E, HCoV-OC43 and HKU1 cause mild to severe respiratory infections. The viral diseases induced by mammalian and avian viruses from Coronaviridae family pose significant economic and public health burdens. Due to increasing reports of viral resistance, co-infections and the emergence of viral epidemics such as COVID-19, available antiviral drugs show low or no efficacy, and the production of new treatments or vaccines are also challenging. Therefore, demand for the development of novel antivirals has considerably increased. In recent years, antiviral peptides have generated increasing interest as they are from natural and computational sources, are highly specific and effective, and possess the broad-spectrum activity with minimum side effects. Here, we have made an effort to compile and review the antiviral peptides with activity against Coronaviridae family viruses. They were divided into different categories according to their action mechanisms, including binding/attachment inhibitors, fusion and entry inhibitors, viral enzyme inhibitors, replication inhibitors and the peptides with direct and indirect effects on the viruses. Reported studies suggest optimism with regard to the design and production of therapeutically promising antiviral drugs. This review aims to summarize data relating to antiviral peptides particularly with respect to their applicability for development as novel treatments.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus/drug effects , Peptides/pharmacology , Antiviral Agents/pharmacokinetics , Peptides/pharmacokinetics , Virus Internalization/drug effects
3.
Emerg Microbes Infect ; 10(1): 317-330, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1075417

ABSTRACT

Coronavirus disease 2019 (COVID-19) is an ongoing pandemic that lacks effective therapeutic interventions. SARS-CoV-2 infects ACE2-expressing cells and gains cell entry through either direct plasma membrane fusion or endocytosis. Recent studies have shown that in addition to ACE2, heparan sulfate proteoglycans (HSPGs) also play an important role in SARS-CoV-2 cell attachment by serving as an attachment factor. Binding of viral spike protein to HSPGs leads to the enrichment of local concentration for the subsequent specific binding with ACE2. We therefore hypothesize that blocking the interactions between viral spike protein and the HSPGs will lead to inhibition of viral replication. In this study, we report our findings of the broad-spectrum antiviral activity and the mechanism of action of lactoferrin (LF) against multiple common human coronaviruses as well as SARS-CoV-2. Our study has shown that LF has broad-spectrum antiviral activity against SARS-CoV-2, HCoV-OC43, HCoV-NL63, and HCoV-229E in cell culture, and bovine lactoferrin (BLF) is more potent than human lactoferrin. Mechanistic studies revealed that BLF binds to HSPGs, thereby blocking viral attachment to the host cell. The antiviral activity of BLF can be antagonized by the HSPG mimetic heparin. Combination therapy experiment showed that the antiviral activity of LF is synergistic with remdesivir in cell culture. Molecular modelling suggests that the N-terminal positively charged region in BLF (residues 17-41) confers the binding to HSPGs. Overall, LF appears to be a promising drug candidate for COVID-19 that warrants further investigation.


Subject(s)
/antagonists & inhibitors , Antiviral Agents/pharmacology , Coronavirus/drug effects , Heparan Sulfate Proteoglycans/metabolism , Lactoferrin/pharmacology , /drug effects , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/pharmacology , Alanine/analogs & derivatives , Alanine/pharmacology , Animals , Cattle , Cell Line , Cells, Cultured , Drug Delivery Systems , Drug Synergism , Heparin/metabolism , Humans , Microbial Sensitivity Tests , Virus Attachment/drug effects
5.
J Virol Methods ; 290: 114070, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-1046238

ABSTRACT

Viral infections are one of the main cause of diseases worldwide due to the rising trends of migration, urbanization and global mobility of humans. The outbreak of corona virus diseases caused by SARS-CoV (year 2003), MERS-CoV (year 2012) and SARS-CoV-2 (year 2019) raised global health concerns. The side effects associated with the conventional drugs and increase in cases of anti-microbial resistance have led the researchers to switch to natural sources, especially plants, as they have immense potential to be used as antiviral agents. The aim of the article is to summarize the evidences of the bioactive phytocompounds from different plants as an effective alternative for the treatment of infections caused by coronaviruses. However, the use of most plant compounds succumbs to limitations due to lack of experimental evidences and safety studies. Therefore, further research and studies are required to validate their therapeutic uses for wide application of plant-based medicine, including anti-virals.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus Infections/virology , Coronavirus/drug effects , Phytochemicals/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/therapeutic use , Coronavirus/classification , Coronavirus/physiology , Coronavirus Infections/diagnosis , Coronavirus Infections/drug therapy , Genome, Viral , Humans , Phytochemicals/chemistry , Phytochemicals/therapeutic use , Plants, Medicinal/chemistry , Viral Proteins/antagonists & inhibitors , Viral Proteins/metabolism
6.
Sheng Wu Gong Cheng Xue Bao ; 36(4): 605-611, 2020 Apr 25.
Article in Chinese | MEDLINE | ID: covidwho-1024807

ABSTRACT

Cyclophilin A (CypA) is a widely distributed and highly conserved protein in organisms. It has peptidyl-prolyl cis/trans isomerase activity and is a receptor for cyclosporin A (CsA). Coronaviruses are enveloped, single-stranded, positive-sense RNA viruses. Seven types of coronaviruses are currently known to infect humans, among which SARS-CoV, MERS-CoV, and SARS-CoV-2 are fatal for humans. It is well established that CypA is essential for the replication of various coronaviruses such as SARS-CoV, CoV-229E, CoV-NL63, and FCoV. Additionally, CsA and its derivatives (ALV, NIM811, etc.) have obvious inhibitory effects on a variety of coronaviruses. These results suggest that CypA is a potential antiviral target and the existing drug CsA might be used as an anti-coronavirus drug. At the end of 2019, SARS-CoV-2 raged in China, which seriously theatern human health and causes huge economic lases. In view of this, we describe the effects of CypA on the replication of coronaviruses and the antiviral activities of its inhibitors, which will provide the scientific basis and ideas for the development of antiviral drugs for SARS-CoV-2.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus Infections , Coronavirus/drug effects , Coronavirus/growth & development , Cyclophilin A/antagonists & inhibitors , Cyclosporine/pharmacology , Cyclosporine/therapeutic use , Pandemics , Pneumonia, Viral , Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , Betacoronavirus/growth & development , Coronavirus Infections/drug therapy , Coronavirus Infections/epidemiology , Coronavirus Infections/virology , Cyclosporine/chemistry , Humans , Pneumonia, Viral/drug therapy , Pneumonia, Viral/epidemiology , Pneumonia, Viral/virology , SARS Virus/drug effects , SARS Virus/growth & development , Virus Replication/drug effects
7.
Pharmacol Res Perspect ; 9(1): e00691, 2021 02.
Article in English | MEDLINE | ID: covidwho-996298

ABSTRACT

Coronaviruses represent global health threat. In this century, they have already caused two epidemics and one serious pandemic. Although, at present, there are no approved drugs and therapies for the treatment and prevention of human coronaviruses, several agents, FDA-approved, and preclinical, have shown in vitro and/or in vivo antiviral activity. An in-depth analysis of the current situation leads to the identification of several potential drugs that could have an impact on the fight against coronaviruses infections. In this review, we discuss the virology of human coronaviruses highlighting the main biological targets and summarize the current state-of-the-art of possible therapeutic options to inhibit coronaviruses infections. We mostly focus on FDA-approved and preclinical drugs targeting viral conserved elements.


Subject(s)
/metabolism , Coronavirus Infections/metabolism , Coronavirus/metabolism , Dipeptidyl Peptidase 4/metabolism , Severe Acute Respiratory Syndrome/metabolism , /antagonists & inhibitors , Angiotensin-Converting Enzyme Inhibitors/administration & dosage , Angiotensin-Converting Enzyme Inhibitors/metabolism , Animals , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Anti-Inflammatory Agents, Non-Steroidal/metabolism , Antiviral Agents/administration & dosage , Antiviral Agents/metabolism , Azoles/administration & dosage , Azoles/metabolism , Coronavirus/drug effects , Coronavirus Infections/drug therapy , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/metabolism , Humans , Naphthoquinones/administration & dosage , Naphthoquinones/metabolism , Organoselenium Compounds/administration & dosage , Organoselenium Compounds/metabolism , Severe Acute Respiratory Syndrome/drug therapy
8.
Virology ; 554: 75-82, 2021 02.
Article in English | MEDLINE | ID: covidwho-989370

ABSTRACT

Human population growth, climate change, and globalization are accelerating the emergence of novel pathogenic viruses. In the past two decades alone, three such members of the coronavirus family have posed serious threats, spurring intense efforts to understand their biology as a way to identify targetable vulnerabilities. Coronaviruses use a programmed -1 ribosomal frameshift (-1 PRF) mechanism to direct synthesis of their replicase proteins. This is a critical switch in their replication program that can be therapeutically targeted. Here, we discuss how nearly half a century of research into -1 PRF have provided insight into the virological importance of -1 PRF, the molecular mechanisms that drive it, and approaches that can be used to manipulate it towards therapeutic outcomes with particular emphasis on SARS-CoV-2.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus/drug effects , Coronavirus/genetics , Frameshifting, Ribosomal/drug effects , Antiviral Agents/chemistry , Antiviral Agents/therapeutic use , Coronavirus/growth & development , Coronavirus/physiology , Coronavirus Infections/drug therapy , Frameshifting, Ribosomal/genetics , Frameshifting, Ribosomal/physiology , Gene Expression Regulation, Viral , Humans , Mutation , Nucleic Acid Conformation , RNA, Viral/chemistry , RNA, Viral/genetics , RNA, Viral/metabolism , /genetics , /physiology , Virus Replication
9.
J Evid Based Integr Med ; 25: 2515690X20932523, 2020.
Article in English | MEDLINE | ID: covidwho-979748

ABSTRACT

The coronavirus (SARS-CoV-2), which causes COVID-19, is a betacoronavirus closely related to the human severe acute respiratory syndrome (SARS)-coronavirus (SARS-CoV). The recent COVID-19 outbreak created an urgent need for treatment. To expedite the development of such treatment, pharmaceutical companies and government agencies are currently testing several existing drugs for their effect on the virus. Gene-Eden-VIR and Novirin are natural, broad-spectrum, antiviral treatments proven to be safe and effective in several clinical studies. In this article, we present evidence indicating that the 5 Gene-Eden-VIR/Novirin ingredients have anti-betacoronavirus, and specifically, anti-SARS-CoV effects. We consider this evidence as a first indication of the anti-coronavirus effects of Gene-Eden-VIR/Novirin. Next, we are planning to conduct a clinical study with users of the treatments to test the effects of Gene-Eden-VIR/Novirin on individuals at risk and those infected with the virus.


Subject(s)
Antiviral Agents/therapeutic use , Betacoronavirus , Coronavirus Infections/drug therapy , Plant Extracts/therapeutic use , Pneumonia, Viral/drug therapy , Quercetin/therapeutic use , Selenium/therapeutic use , Coronavirus/drug effects , Coronavirus Infections/epidemiology , Drug Combinations , Humans , Pandemics , Pneumonia, Viral/epidemiology
10.
PLoS Pathog ; 16(11): e1009013, 2020 11.
Article in English | MEDLINE | ID: covidwho-902060

ABSTRACT

Over the last 2 decades, several coronaviruses (CoVs) have crossed the species barrier into humans, causing highly prevalent and severe respiratory diseases, often with fatal outcomes. CoVs are a large group of enveloped, single-stranded, positive-sense RNA viruses, which encode large replicase polyproteins that are processed by viral peptidases to generate the nonstructural proteins (Nsps) that mediate viral RNA synthesis. Papain-like peptidases (PLPs) and chymotrypsin-like cysteine 3C-like peptidase are essential for coronaviral replication and represent attractive antiviral drug targets. Furthermore, CoVs utilize the activation of their envelope spike glycoproteins by host cell peptidases to gain entry into cells. CoVs have evolved multiple strategies for spike protein activation, including the utilization of lysosomal cysteine cathepsins. In this review, viral and host peptidases involved in CoV cell entry and replication are discussed in depth, with an emphasis on papain-like cysteine cathepsins. Furthermore, important findings on cysteine peptidase inhibitors with regard to virus attenuation are highlighted as well as the potential of such inhibitors for future treatment strategies for CoV-related diseases.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus Infections/virology , Coronavirus/drug effects , Cysteine Proteinase Inhibitors/pharmacology , Virus Internalization/drug effects , Animals , Coronavirus Infections/drug therapy , Humans , Virus Replication/drug effects
11.
Epidemiol Infect ; 148: e229, 2020 09 29.
Article in English | MEDLINE | ID: covidwho-851179

ABSTRACT

The pandemic due to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has emerged as a serious global public health issue. Since the start of the outbreak, the importance of hand-hygiene and respiratory protection to prevent the spread of the virus has been the prime focus for infection control. Health regulatory organisations have produced guidelines for the formulation of hand sanitisers to the manufacturing industries. This review summarises the studies on alcohol-based hand sanitisers and their disinfectant activity against SARS-CoV-2 and related viruses. The literature shows that the type and concentration of alcohol, formulation and nature of product, presence of excipients, applied volume, contact time and viral contamination load are critical factors that determine the effectiveness of hand sanitisers.


Subject(s)
Alcohols/chemistry , Betacoronavirus/drug effects , Hand Sanitizers/chemistry , Hand Sanitizers/standards , Alcohols/pharmacology , Betacoronavirus/chemistry , Coronavirus/chemistry , Coronavirus/drug effects , Coronavirus Infections/epidemiology , Coronavirus Infections/prevention & control , Drug Contamination , Hand Sanitizers/pharmacology , Humans , Pandemics/prevention & control , Pneumonia, Viral/epidemiology , Pneumonia, Viral/prevention & control
13.
Bratisl Lek Listy ; 121(9): 686, 2020.
Article in English | MEDLINE | ID: covidwho-807379
14.
Int J Environ Res Public Health ; 17(18)2020 09 19.
Article in English | MEDLINE | ID: covidwho-789454

ABSTRACT

Our objective was to compare clinical protocols for the treatment of the novel coronavirus disease 2019 (COVID-19) among different hospitals in Andalusia, Spain. We reviewed the current COVID-19 protocols of the 15 largest hospitals in Andalusia. Antiviral treatment, empirical antibacterial agents, adjunctive therapies, anticoagulant treatment, supportive care, hospital organization, and discharge recommendations were analyzed. All protocols included were the latest updates as of July 2020. Hydroxychloroquine in monotherapy was the most frequent antiviral drug recommended for mild respiratory illness with clinical risk factors (33.3%). Combined hydroxychloroquine with azithromycin or lopinavir/ritonavir was found in 40% of protocols. The recommended treatment for patients with mild and moderate pneumonias was different antiviral combinations including hydroxychloroquine plus azithromycin (93.3%) or hydroxychloroquine plus lopinavir/ritonavir (79.9%). Different combinations of hydroxychloroquine and lopinavir/ritonavir (46.7%) and triple therapy with hydroxychloroquine, azithromycin, and lopinavir/ritonavir (40%) were the most recommended treatments for patients with severe pneumonia. There were five corticosteroid regimens, which used dexamethasone, methylprednisolone, or prednisone, with different doses and treatment durations. Anakinra was included in seven protocols with six different regimens. All protocols included prophylactic heparin and therapeutic doses for thromboembolism. Higher prophylactic doses of heparin for high-risk patients and therapeutic doses for patients in critical condition were included in 53.3% and 33.3% of protocols, respectively. This study showed that COVID-19 protocols varied widely in several aspects (antiviral treatment, corticosteroids, anakinra, and anticoagulation for high risk of thrombosis or critical situation). Rigorous randomized clinical trials on the proposed treatments are needed to provide consistent evidence.


Subject(s)
Antiviral Agents/therapeutic use , Coronavirus Infections/drug therapy , Coronavirus , Pandemics , Pneumonia, Viral/drug therapy , Betacoronavirus , Clinical Protocols , Coronavirus/drug effects , Coronavirus/isolation & purification , Coronavirus Infections/epidemiology , Drug Combinations , Humans , Pneumonia, Viral/epidemiology , Spain/epidemiology , Treatment Outcome
15.
Rev Assoc Med Bras (1992) ; 66Suppl 2(Suppl 2): 124-129, 2020.
Article in English | MEDLINE | ID: covidwho-788986

ABSTRACT

An alarming fact was revealed by recent publications concerning disinfectants: chlorhexidine digluconate is ineffective for disinfecting surfaces contaminated by the new coronavirus. This is a finding that requires immediate disclosure since this substance is widely used for the disinfection of hands and forearms of surgeons and auxiliaries and in the antisepsis of patients in minimally invasive procedures commonly performed in hospital environments. The objective of this study is to compare the different disinfectants used for disinfection on several surfaces, in a review of worldwide works. Scientific studies were researched in the BVS (Virtual Health Library), PubMed, Medline, and ANVISA (National Health Surveillance Agency) databases. The following agents were studied: alcohol 62-71%, hydrogen peroxide 0.5%, sodium hypochlorite 0.1%, benzalkonium chloride 0.05-0.2%, povidone-iodine 10%, and chlorhexidine digluconate 0.02%, on metal, aluminum, wood, paper, glass, plastic, PVC, silicone, latex (gloves), disposable gowns, ceramic, and Teflon surfaces. Studies have shown that chlorhexidine digluconate is ineffective for inactivating some coronavirus subtypes, suggesting that it is also ineffective to the new coronavirus.


Subject(s)
Anti-Infective Agents, Local/pharmacology , Chlorhexidine/pharmacology , Coronavirus/drug effects , Disinfectants/pharmacology , Povidone-Iodine/pharmacology , Coronavirus Infections/epidemiology , Disinfection , Humans , Pandemics , Pneumonia, Viral/epidemiology
16.
Viruses ; 12(9)2020 09 09.
Article in English | MEDLINE | ID: covidwho-760953

ABSTRACT

BACKGROUND: To prioritize the development of antiviral compounds, it is necessary to compare their relative preclinical activity and clinical efficacy. METHODS: We reviewed in vitro, animal model, and clinical studies of candidate anti-coronavirus compounds and placed extracted data in an online relational database. RESULTS: As of August 2020, the Coronavirus Antiviral Research Database (CoV-RDB; covdb.stanford.edu) contained over 2800 cell culture, entry assay, and biochemical experiments, 259 animal model studies, and 73 clinical studies from over 400 published papers. SARS-CoV-2, SARS-CoV, and MERS-CoV account for 85% of the data. Approximately 75% of experiments involved compounds with known or likely mechanisms of action, including monoclonal antibodies and receptor binding inhibitors (21%), viral protease inhibitors (17%), miscellaneous host-acting inhibitors (10%), polymerase inhibitors (9%), interferons (7%), fusion inhibitors (5%), and host protease inhibitors (5%). Of 975 compounds with known or likely mechanism, 135 (14%) are licensed in the U.S. for other indications, 197 (20%) are licensed outside the U.S. or are in human trials, and 595 (61%) are pre-clinical investigational compounds. CONCLUSION: CoV-RDB facilitates comparisons between different candidate antiviral compounds, thereby helping scientists, clinical investigators, public health officials, and funding agencies prioritize the most promising compounds and repurposed drugs for further development.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Databases, Factual , Pneumonia, Viral/drug therapy , Animals , Antiviral Agents/therapeutic use , Cells, Cultured , Clinical Trials as Topic , Coronavirus/drug effects , Drug Evaluation, Preclinical , Humans , Mammals , Models, Animal , Pandemics , Registries , Species Specificity , User-Computer Interface
17.
Molecules ; 25(18)2020 Sep 08.
Article in English | MEDLINE | ID: covidwho-760942

ABSTRACT

The epidemic, caused by SARS-CoV-2 at the beginning of 2020, led us to a serious change in our lifestyle that for about three months has confined us to our homes, far from our laboratory routine. In this period, the belief that the work of a researcher should never stop has been the driving force in writing the present paper. It aims at reviewing the recent scientific knowledge about in vitro experimental data that focused on the antiviral role of phenols and polyphenols against different species of coronaviruses (CoVs), pointing up the viral targets potentially involved. In the current literature scenario, the papain-like and the 3-chymotrypsin-like proteases seem to be the most deeply investigated and a number of isolated natural (poly)phenols has been screened for their efficacy.


Subject(s)
Antiviral Agents/pharmacology , Biomedical Research/trends , Coronavirus/drug effects , Polyphenols/pharmacology , Animals , Betacoronavirus/drug effects , Chymases/therapeutic use , Humans
18.
Virol J ; 17(1): 136, 2020 09 09.
Article in English | MEDLINE | ID: covidwho-751192

ABSTRACT

BACKGROUND: Coronaviruses (CoVs) were long thought to only cause mild respiratory and gastrointestinal symptoms in humans but outbreaks of Middle East Respiratory Syndrome (MERS)-CoV, Severe Acute Respiratory Syndrome (SARS)-CoV-1, and the recently identified SARS-CoV-2 have cemented their zoonotic potential and their capacity to cause serious morbidity and mortality, with case fatality rates ranging from 4 to 35%. Currently, no specific prophylaxis or treatment is available for CoV infections. Therefore we investigated the virucidal and antiviral potential of Echinacea purpurea (Echinaforce®) against human coronavirus (HCoV) 229E, highly pathogenic MERS- and SARS-CoVs, as well as the newly identified SARS-CoV-2, in vitro. METHODS: To evaluate the antiviral potential of the extract, we pre-treated virus particles and cells and evaluated remaining infectivity by limited dilution. Furthermore, we exposed cells to the extract after infection to further evaluate its potential as a prophylaxis and treatment against coronaviruses. We also determined the protective effect of Echinaforce® in re-constituted nasal epithelium. RESULTS: In the current study, we found that HCoV-229E was irreversibly inactivated when exposed to Echinaforce® at 3.2 µg/ml IC50. Pre-treatment of cell lines, however, did not inhibit infection with HCoV-229E and post-infection treatment had only a marginal effect on virus propagation at 50 µg/ml. However, we did observe a protective effect in an organotypic respiratory cell culture system by exposing pre-treated respiratory epithelium to droplets of HCoV-229E, imitating a natural infection. The observed virucidal activity of Echinaforce® was not restricted to common cold coronaviruses, as both SARS-CoV-1 and MERS-CoVs were inactivated at comparable concentrations. Finally, the causative agent of COVID-19, SARS-CoV-2 was also inactivated upon treatment with 50µg/ml Echinaforce®. CONCLUSIONS: These results show that Echinaforce® is virucidal against HCoV-229E, upon direct contact and in an organotypic cell culture model. Furthermore, MERS-CoV and both SARS-CoV-1 and SARS-CoV-2 were inactivated at similar concentrations of the extract. Therefore we hypothesize that Echinacea purpurea preparations, such as Echinaforce®, could be effective as prophylactic treatment for all CoVs due to their structural similarities.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Coronavirus 229E, Human/drug effects , Coronavirus Infections/drug therapy , Coronavirus/drug effects , Plant Extracts/pharmacology , Plant Extracts/therapeutic use , Animals , Cell Line , Chlorocebus aethiops , Common Cold/drug therapy , Common Cold/virology , Coronavirus Infections/virology , Humans , Middle East Respiratory Syndrome Coronavirus/drug effects , Pandemics , Pneumonia, Viral/drug therapy , Pneumonia, Viral/virology , RNA Viruses/drug effects , Randomized Controlled Trials as Topic , Severe Acute Respiratory Syndrome/drug therapy , Severe Acute Respiratory Syndrome/virology , Vero Cells
19.
Phytomedicine ; 78: 153296, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-747894

ABSTRACT

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has extensively and rapidly spread in the world, causing an outbreak of acute infectious pneumonia. However, no specific antiviral drugs or vaccines can be used. Phillyrin (KD-1), a representative ingredient of Forsythia suspensa, possesses anti-inflammatory, anti-oxidant, and antiviral activities. However, little is known about the antiviral abilities and mechanism of KD-1 against SARS-CoV-2 and human coronavirus 229E (HCoV-229E). PURPOSE: The study was designed to investigate the antiviral and anti-inflammatory activities of KD-1 against the novel SARS-CoV-2 and HCoV-229E and its potential effect in regulating host immune response in vitro. METHODS: The antiviral activities of KD-1 against SARS-CoV-2 and HCoV-229E were assessed in Vero E6 cells using cytopathic effect and plaque-reduction assay. Proinflammatory cytokine expression levels upon infection with SARS-CoV-2 and HCoV-229E infection in Huh-7 cells were measured by real-time quantitative PCR assays. Western blot assay was used to determine the protein expression of nuclear factor kappa B (NF-κB) p65, p-NF-κB p65, IκBα, and p-IκBα in Huh-7 cells, which are the key targets of the NF-κB pathway. RESULTS: KD-1 could significantly inhibit SARS-CoV-2 and HCoV-229E replication in vitro. KD-1 could also markedly reduce the production of proinflammatory cytokines (TNF-α, IL-6, IL-1ß, MCP-1, and IP-10) at the mRNA levels. Moreover, KD-1 could significantly reduce the protein expression of p-NF-κB p65, NF-κB p65, and p-IκBα, while increasing the expression of IκBα in Huh-7 cells. CONCLUSIONS: KD-1 could significantly inhibit virus proliferation in vitro, the up-regulated expression of proinflammatory cytokines induced by SARS-CoV-2 and HCoV-229E by regulating the activity of the NF-кB signaling pathway. Our findings indicated that KD-1 protected against virus attack and can thus be used as a novel strategy for controlling the coronavirus disease 2019.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Coronavirus 229E, Human/drug effects , Coronavirus Infections , Glucosides/pharmacology , NF-kappa B/metabolism , Pandemics , Pneumonia, Viral , Animals , Chlorocebus aethiops , Coronavirus/drug effects , Coronavirus Infections/metabolism , Coronavirus Infections/virology , Cytokines/metabolism , Forsythia/chemistry , Humans , Phytotherapy , Plant Extracts/pharmacology , Pneumonia, Viral/metabolism , Pneumonia, Viral/virology , Severe Acute Respiratory Syndrome/virology , Signal Transduction/drug effects , Vero Cells , Virus Replication/drug effects
20.
Nat Commun ; 11(1): 4252, 2020 08 25.
Article in English | MEDLINE | ID: covidwho-741685

ABSTRACT

The 2019 novel respiratory virus (SARS-CoV-2) causes COVID-19 with rapid global socioeconomic disruptions and disease burden to healthcare. The COVID-19 and previous emerging virus outbreaks highlight the urgent need for broad-spectrum antivirals. Here, we show that a defensin-like peptide P9R exhibited potent antiviral activity against pH-dependent viruses that require endosomal acidification for virus infection, including the enveloped pandemic A(H1N1)pdm09 virus, avian influenza A(H7N9) virus, coronaviruses (SARS-CoV-2, MERS-CoV and SARS-CoV), and the non-enveloped rhinovirus. P9R can significantly protect mice from lethal challenge by A(H1N1)pdm09 virus and shows low possibility to cause drug-resistant virus. Mechanistic studies indicate that the antiviral activity of P9R depends on the direct binding to viruses and the inhibition of virus-host endosomal acidification, which provides a proof of concept that virus-binding alkaline peptides can broadly inhibit pH-dependent viruses. These results suggest that the dual-functional virus- and host-targeting P9R can be a promising candidate for combating pH-dependent respiratory viruses.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus/drug effects , Influenza A virus/drug effects , Peptides/pharmacology , Amino Acid Sequence , Animals , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Antiviral Agents/therapeutic use , Cell Line , Endosomes/chemistry , Endosomes/drug effects , Female , Humans , Hydrogen-Ion Concentration , Influenza A virus/metabolism , Mice , Mice, Inbred BALB C , Orthomyxoviridae Infections/drug therapy , Orthomyxoviridae Infections/metabolism , Peptides/chemistry , Peptides/metabolism , Peptides/therapeutic use , Protein Binding , Protein Conformation , Rhinovirus/drug effects , Rhinovirus/metabolism , Viral Load/drug effects , Virus Replication/drug effects
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