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1.
Molecules ; 25(17)2020 Aug 27.
Article in English | MEDLINE | ID: covidwho-737517

ABSTRACT

Three types of new coronaviruses (CoVs) have been identified recently as the causative viruses for the severe pneumonia-like respiratory illnesses, severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and corona-virus disease 2019 (COVID-19). Neither therapeutic agents nor vaccines have been developed to date, which is a major drawback in controlling the present global pandemic of COVID-19 caused by SARS coronavirus 2 (SARS-CoV-2) and has resulted in more than 20,439,814 cases and 744,385 deaths. Each of the 3C-like (3CL) proteases of the three CoVs is essential for the proliferation of the CoVs, and an inhibitor of the 3CL protease (3CLpro) is thought to be an ideal therapeutic agent against SARS, MERS, or COVID-19. Among these, SARS-CoV is the first corona-virus isolated and has been studied in detail since the first pandemic in 2003. This article briefly reviews a series of studies on SARS-CoV, focusing on the development of inhibitors for the SARS-CoV 3CLpro based on molecular interactions with the 3CL protease. Our recent approach, based on the structure-based rational design of a novel scaffold for SARS-CoV 3CLpro inhibitor, is also included. The achievements summarized in this short review would be useful for the design of a variety of novel inhibitors for corona-viruses, including SARS-CoV-2.


Subject(s)
Antiviral Agents/chemistry , Betacoronavirus/chemistry , Middle East Respiratory Syndrome Coronavirus/pathogenicity , Protease Inhibitors/chemistry , SARS Virus/pathogenicity , Viral Nonstructural Proteins/antagonists & inhibitors , Antiviral Agents/classification , Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , Betacoronavirus/enzymology , Catalytic Domain , Coronavirus Infections/drug therapy , Crystallography, X-Ray , Cysteine Endopeptidases/chemistry , Cysteine Endopeptidases/genetics , Cysteine Endopeptidases/metabolism , Humans , Kinetics , Middle East Respiratory Syndrome Coronavirus/genetics , Middle East Respiratory Syndrome Coronavirus/metabolism , Molecular Docking Simulation , Pandemics , Pneumonia, Viral/drug therapy , Protease Inhibitors/classification , Protease Inhibitors/therapeutic use , Protein Binding , Protein Conformation, alpha-Helical , Protein Conformation, beta-Strand , Protein Interaction Domains and Motifs , SARS Virus/genetics , SARS Virus/metabolism , Severe Acute Respiratory Syndrome/drug therapy , Substrate Specificity , Thermodynamics , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/genetics , Viral Nonstructural Proteins/metabolism
2.
Am J Physiol Cell Physiol ; 319(3): C500-C509, 2020 09 01.
Article in English | MEDLINE | ID: covidwho-656622

ABSTRACT

Severe acute respiratory syndrome coronavirus (SARS-CoV), an enveloped virus with a positive-sense single-stranded RNA genome, facilitates the host cell entry through intricate interactions with proteins and lipids of the cell membrane. The detailed molecular mechanism involves binding to the host cell receptor and fusion at the plasma membrane or after being trafficked to late endosomes under favorable environmental conditions. A crucial event in the process is the proteolytic cleavage of the viral spike protein by the host's endogenous proteases that releases the fusion peptide enabling fusion with the host cellular membrane system. The present review details the mechanism of viral fusion with the host and highlights the therapeutic options that prevent SARS-CoV-2 entry in humans.


Subject(s)
Betacoronavirus/metabolism , Cell Membrane/metabolism , Coronavirus Infections/metabolism , Coronavirus Infections/prevention & control , Pandemics/prevention & control , Pneumonia, Viral/metabolism , Pneumonia, Viral/prevention & control , Viral Fusion Proteins/metabolism , Amino Acid Sequence , Animals , Betacoronavirus/drug effects , Cell Membrane/drug effects , Cell Membrane/virology , Humans , Peptidyl-Dipeptidase A/metabolism , Protease Inhibitors/pharmacology , Protease Inhibitors/therapeutic use , Protein Binding/drug effects , Protein Binding/physiology , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Spike Glycoprotein, Coronavirus/metabolism , Viral Fusion Proteins/drug effects
3.
Mol Neurobiol ; 57(10): 4106-4116, 2020 Oct.
Article in English | MEDLINE | ID: covidwho-645016

ABSTRACT

The coronavirus disease of 2019 (COVID-19) is a pandemic disease that has taken the lives of many around the world. It is caused by severe acute respiratory syndrome-corona virus-2 (SARS-CoV-2). To date, the USA, Italy, Spain, France, Russia, and the UK have been hit the hardest by the virus. However, death counts are still rising. Some nations have managed to "flatten" the death rate via protective measures such physical distancing, quarantine measures, and therapeutic management. The structure of the SARS-CoV-2 virus comprises of S proteins, M proteins, E proteins, hemagglutinin esterases, nucleocapsid proteins, and a 30-kb RNA genome. Viral proteases cleave these polyproteins and RNA-dependent polymerases replicate the genome. Currently, there are no effective therapies against this new disease. Numerous investigators are developing novel protease inhibitors, some of which have made it into clinical trials. Researchers are also attempting to develop a vaccine. In this review paper, we discuss the latest therapeutic developments against COVID-19. Graphical Abstract.


Subject(s)
Antiviral Agents/therapeutic use , Coronavirus Infections/therapy , Pneumonia, Viral/therapy , Protease Inhibitors/therapeutic use , Viral Vaccines/therapeutic use , Betacoronavirus , Coronavirus Infections/epidemiology , Coronavirus Infections/prevention & control , Humans , Pandemics/prevention & control , Pneumonia, Viral/epidemiology
5.
Commun Biol ; 3(1): 374, 2020 07 08.
Article in English | MEDLINE | ID: covidwho-640282

ABSTRACT

The recent outbreak of infections and the pandemic caused by SARS-CoV-2 represent one of the most severe threats to human health in more than a century. Emerging data from the United States and elsewhere suggest that the disease is more severe in men. Knowledge gained, and lessons learned, from studies of the biological interactions and molecular links that may explain the reasons for the greater severity of disease in men, and specifically in the age group at risk for prostate cancer, will lead to better management of COVID-19 in prostate cancer patients. Such information will be indispensable in the current and post-pandemic scenarios.


Subject(s)
Betacoronavirus , Coronavirus Infections/epidemiology , Pandemics , Pneumonia, Viral/epidemiology , Prostatic Neoplasms/epidemiology , Sex Distribution , Antineoplastic Agents, Hormonal/therapeutic use , Antiviral Agents/therapeutic use , Betacoronavirus/physiology , Betacoronavirus/ultrastructure , Comorbidity , Coronavirus Infections/drug therapy , Coronavirus Infections/immunology , Disease Susceptibility , Drug Repositioning , Female , Forecasting , Gonadal Steroid Hormones/physiology , Humans , Male , Neoplasm Proteins/antagonists & inhibitors , Neoplasm Proteins/biosynthesis , Neoplasm Proteins/physiology , Peptidyl-Dipeptidase A/physiology , Pneumonia, Viral/drug therapy , Pneumonia, Viral/immunology , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/metabolism , Protease Inhibitors/therapeutic use , Receptors, Virus/drug effects , Receptors, Virus/physiology , Risk Factors , Serine Endopeptidases/biosynthesis , Serine Endopeptidases/physiology , United States/epidemiology , Virus Internalization
6.
Biomolecules ; 10(6)2020 Jun 24.
Article in English | MEDLINE | ID: covidwho-613362

ABSTRACT

The pandemic associated with Severe Acute Respiratory Syndrome Coronavirus type 2 (SARS-CoV2) and its disease named COVID-19 challenged the scientific community to discover effective therapeutic solutions in a short period. Repurposing existing drugs is one viable approach that emphasizes speed during these urgent times. Famotidine, a class A G protein-coupled receptor antagonist used for the treatment of gastroesophageal reflux was recently identified in an in silico screening. Additionally, a recent retrospective clinical report showed that the treatment with famotidine provided a good outcome in patients infected with SARS-CoV2. A clinical trial testing effectiveness of famotidine in combination with hydroxychloroquine is currently ongoing in the United States (US). In the 1990s, famotidine was described as an antiviral agent against human immunodeficiency virus (HIV). Interestingly, some HIV protease inhibitors are presently being used against SARS-CoV2. However, it is not clear if famotidine could be effective against SARS-CoV2. Thus, by using a computational analysis, we aimed to examine if the antiviral effect of famotidine could be related to the inhibition of proteases involved in the virus replication. Our results showed that famotidine could interact within the catalytic site of the three proteases associated with SARS-CoV2 replication. However, weak binding affinity of famotidine to these proteases suggests that a successful famotidine therapy could likely be achieved only in combination with other antiviral drugs. Finally, analysis of famotidine's pharmacokinetic parameters indicated that its effect against SARS-CoV2 infection could be reached only upon intravenous administration. This work will contribute to the pharmacological knowledge of famotidine as an antiviral agent against SARS-CoV2.


Subject(s)
Antiviral Agents/therapeutic use , Coronavirus Infections/drug therapy , Famotidine/therapeutic use , Pneumonia, Viral/drug therapy , Receptors, G-Protein-Coupled/antagonists & inhibitors , Administration, Intravenous , Antiviral Agents/administration & dosage , Antiviral Agents/pharmacokinetics , Computer Simulation , Drug Repositioning , Famotidine/administration & dosage , Famotidine/pharmacokinetics , Humans , Models, Molecular , Molecular Docking Simulation , Pandemics , Protease Inhibitors/administration & dosage , Protease Inhibitors/pharmacokinetics , Protease Inhibitors/therapeutic use , Virus Replication/drug effects
9.
Int J Antimicrob Agents ; 56(2): 106055, 2020 Aug.
Article in English | MEDLINE | ID: covidwho-593424

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), similar to SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV), which belong to the same Betacoronavirus genus, induces severe acute respiratory disease that is a threat to human health. Since the outbreak of infection by SARS-CoV-2 began, which causes coronavirus disease 2019 (COVID-19), the disease has rapidly spread worldwide. Thus, a search for effective drugs able to inhibit SARS-CoV-2 has become a global pursuit. The 3C-like protease (3CLpro), which hydrolyses viral polyproteins to produce functional proteins, is essential for coronavirus replication and is considered an important therapeutic target for diseases caused by coronaviruses, including COVID-19. Many 3CLpro inhibitors have been proposed and some new drug candidates have achieved success in preclinical studies. In this review, we briefly describe recent developments in determining the structure of 3CLpro and its function in coronavirus replication and summarise new insights into 3CLpro inhibitors and their mechanisms of action. The clinical application prospects and limitations of 3CLpro inhibitors for COVID-19 treatment are also discussed.


Subject(s)
Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Protease Inhibitors/therapeutic use , Viral Nonstructural Proteins/antagonists & inhibitors , Betacoronavirus , Coronavirus Infections/virology , Cysteine Endopeptidases/chemistry , Humans , Molecular Structure , Pandemics , Pneumonia, Viral/virology , Protease Inhibitors/chemistry , Viral Nonstructural Proteins/chemistry
10.
Free Radic Biol Med ; 156: 107-112, 2020 08 20.
Article in English | MEDLINE | ID: covidwho-620858

ABSTRACT

Ebselen is an organoselenium compound exhibiting hydroperoxide- and peroxynitrite-reducing activity, acting as a glutathione peroxidase and peroxiredoxin enzyme mimetic. Ebselen reacts with a multitude of protein thiols, forming a selenosulfide bond, which results in pleiotropic effects of antiviral, antibacterial and anti-inflammatory nature. The main protease (Mpro) of the corona virus SARS-CoV-2 is a potential drug target, and a screen with over 10,000 compounds identified ebselen as a particularly promising inhibitor of Mpro (Jin, Z. et al. (2020) Nature 582, 289-293). We discuss here the reaction of ebselen with cysteine proteases, the role of ebselen in infections with viruses and with other microorganisms. We also discuss effects of ebselen in lung inflammation. In further research on the inhibition of Mpro in SARS-CoV-2, ebselen can serve as a promising lead compound, if the inhibitory effect is confirmed in intact cells in vivo. Independently of this action, potential beneficial effects of ebselen in COVID-19 are ascribed to a number of targets critical to pathogenesis, such as attenuation of inflammatory oxidants and cytokines.


Subject(s)
Antioxidants/therapeutic use , Antiviral Agents/therapeutic use , Azoles/therapeutic use , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Organoselenium Compounds/therapeutic use , Pandemics , Pneumonia, Viral/drug therapy , Viral Nonstructural Proteins/antagonists & inhibitors , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Betacoronavirus/enzymology , Betacoronavirus/pathogenicity , Binding Sites , Coronavirus Infections/epidemiology , Coronavirus Infections/metabolism , Coronavirus Infections/virology , Cysteine Endopeptidases/chemistry , Cysteine Endopeptidases/metabolism , Host-Pathogen Interactions/drug effects , Host-Pathogen Interactions/genetics , Humans , Lung/drug effects , Lung/metabolism , Lung/pathology , Lung/virology , Models, Molecular , Oxidative Stress/drug effects , Pneumonia, Viral/epidemiology , Pneumonia, Viral/metabolism , Pneumonia, Viral/virology , Protease Inhibitors/therapeutic use , Protein Binding , Protein Structure, Secondary , Reactive Oxygen Species/antagonists & inhibitors , Reactive Oxygen Species/metabolism , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/metabolism
11.
Int J Mol Sci ; 21(11)2020 May 28.
Article in English | MEDLINE | ID: covidwho-401521

ABSTRACT

In the past 17 years, three novel coronaviruses have caused severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and the coronavirus disease 2019 (COVID-19). As emerging infectious diseases, they were characterized by their novel pathogens and transmissibility without available clinical drugs or vaccines. This is especially true for the newly identified COVID-19 caused by SARS coronavirus 2 (SARS-CoV-2) for which, to date, no specific antiviral drugs or vaccines have been approved. Similar to SARS and MERS, the lag time in the development of therapeutics is likely to take months to years. These facts call for the development of broad-spectrum anti-coronavirus drugs targeting a conserved target site. This review will systematically describe potential broad-spectrum coronavirus fusion inhibitors, including antibodies, protease inhibitors, and peptide fusion inhibitors, along with a discussion of their advantages and disadvantages.


Subject(s)
Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Protease Inhibitors/therapeutic use , Viral Fusion Protein Inhibitors/therapeutic use , Animals , Betacoronavirus/physiology , Humans , Protease Inhibitors/adverse effects , Protease Inhibitors/pharmacology , Viral Fusion Protein Inhibitors/adverse effects , Viral Fusion Protein Inhibitors/pharmacology , Virus Internalization/drug effects
12.
Euro Surveill ; 25(18)2020 05.
Article in English | MEDLINE | ID: covidwho-197111

ABSTRACT

Data on features of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in children and adolescents are scarce. We report preliminary results of an Italian multicentre study comprising 168 laboratory-confirmed paediatric cases (median: 2.3 years, range: 1 day-17.7 years, 55.9% males), of which 67.9% were hospitalised and 19.6% had comorbidities. Fever was the most common symptom, gastrointestinal manifestations were frequent; two children required intensive care, five had seizures, 49 received experimental treatments and all recovered.


Subject(s)
Chronic Disease/epidemiology , Coinfection/epidemiology , Coronavirus Infections/diagnosis , Coronavirus/isolation & purification , Pandemics/prevention & control , Pneumonia, Viral/diagnosis , Adolescent , Antiviral Agents/therapeutic use , Betacoronavirus , Child , Child, Preschool , Clinical Laboratory Techniques , Coinfection/virology , Comorbidity , Coronavirus Infections/epidemiology , Coronavirus Infections/therapy , Diarrhea/etiology , Disease Outbreaks , Feces/virology , Female , Fever/etiology , Hospitals, Pediatric , Humans , Immunocompromised Host , Infant , Infant, Newborn , Italy/epidemiology , Male , Noninvasive Ventilation/methods , Pneumonia, Viral/epidemiology , Pneumonia, Viral/therapy , Protease Inhibitors/therapeutic use , Retrospective Studies , Severe Acute Respiratory Syndrome/diagnosis , Severe Acute Respiratory Syndrome/epidemiology , Severe Acute Respiratory Syndrome/therapy , Treatment Outcome
13.
Br J Pharmacol ; 177(14): 3147-3161, 2020 07.
Article in English | MEDLINE | ID: covidwho-176068

ABSTRACT

As of April 9, 2020, a novel coronavirus (SARS-CoV-2) had caused 89,931 deaths and 1,503,900 confirmed cases worldwide, which indicates an increasingly severe and uncontrollable situation. Initially, little was known about the virus. As research continues, we now know the genome structure, epidemiological and clinical characteristics, and pathogenic mechanisms of SARS-CoV-2. Based on this knowledge, potential targets involved in the processes of virus pathogenesis need to be identified, and the discovery or development of drugs based on these potential targets is the most pressing need. Here, we have summarized the potential therapeutic targets involved in virus pathogenesis and discuss the advances, possibilities, and significance of drugs based on these targets for treating SARS-CoV-2. This review will facilitate the identification of potential targets and provide clues for drug development that can be translated into clinical applications for combating SARS-CoV-2.


Subject(s)
Betacoronavirus/genetics , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/therapeutic use , Alanine/analogs & derivatives , Alanine/therapeutic use , Angiotensin II Type 1 Receptor Blockers/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Antiviral Agents/therapeutic use , Basigin/metabolism , Betacoronavirus/metabolism , Betacoronavirus/pathogenicity , Coronavirus Infections/complications , Coronavirus Infections/immunology , Coronavirus Infections/metabolism , Coronavirus Infections/prevention & control , Coronavirus Infections/therapy , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/immunology , Gabexate/analogs & derivatives , Gabexate/therapeutic use , Genome, Viral , Guanidines/therapeutic use , Humans , Immunization, Passive , Immunosuppressive Agents/therapeutic use , Medicine, Chinese Traditional , Nucleic Acid Synthesis Inhibitors/therapeutic use , Pandemics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/complications , Pneumonia, Viral/immunology , Pneumonia, Viral/metabolism , Protease Inhibitors/therapeutic use , RNA Replicase/metabolism , Serine Endopeptidases/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Viral Vaccines , Virus Internalization , Virus Replication
14.
Indian J Pediatr ; 87(6): 433-442, 2020 06.
Article in English | MEDLINE | ID: covidwho-125227

ABSTRACT

COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a major public health crisis threatening humanity at this point in time. Transmission of the infection occurs by inhalation of infected droplets or direct contact with soiled surfaces and fomites. It should be suspected in all symptomatic children who have undertaken international travel in the last 14 d, all hospitalized children with severe acute respiratory illness, and asymptomatic direct and high-risk contacts of a confirmed case. Clinical symptoms are similar to any acute respiratory viral infection with less pronounced nasal symptoms. Disease seems to be milder in children, but situation appears to be changing. Infants and young children had relatively more severe illness than older children. The case fatality rate is low in children. Diagnosis can be confirmed by Reverse transcriptase - Polymerase chain reaction (RT-PCR) on respiratory specimen (commonly nasopharyngeal and oropharyngeal swab). Rapid progress is being made to develop rapid diagnostic tests, which will help ramp up the capacity to test and also reduce the time to getting test results. Management is mainly supportive care. In severe pneumonia and critically ill children, trial of hydroxychloroquine or lopinavir/ritonavir should be considered. As per current policy, children with mild disease also need to be hospitalized; if this is not feasible, these children may be managed on ambulatory basis with strict home isolation. Pneumonia, severe disease and critical illness require admission and aggressive management for acute lung injury and shock and/or multiorgan dysfunction, if present. An early intubation is preferred over non-invasive ventilation or heated, humidified, high flow nasal cannula oxygen, as these may generate aerosols increasing the risk of infection in health care personnel. To prevent post discharge dissemination of infection, home isolation for 1-2 wk may be advised. As of now, no vaccine or specific chemotherapeutic agents are approved for children.


Subject(s)
Acute Lung Injury/etiology , Betacoronavirus/isolation & purification , Coronavirus Infections/epidemiology , Palliative Care , Pneumonia, Viral/therapy , Acute Lung Injury/therapy , Antiviral Agents/therapeutic use , Betacoronavirus/genetics , Child , Child, Preschool , Clinical Laboratory Techniques , Coronavirus Infections/diagnosis , Coronavirus Infections/drug therapy , Coronavirus Infections/prevention & control , Coronavirus Infections/therapy , Coronavirus Infections/virology , Disease Outbreaks/prevention & control , Humans , Hydroxychloroquine/therapeutic use , Infant , Lopinavir/therapeutic use , Pandemics/prevention & control , Pneumonia, Viral/epidemiology , Pneumonia, Viral/virology , Protease Inhibitors/therapeutic use , Respiratory Distress Syndrome, Adult , Reverse Transcriptase Polymerase Chain Reaction , Ritonavir/therapeutic use , Severe Acute Respiratory Syndrome/diagnosis , Severe Acute Respiratory Syndrome/epidemiology , Severe Acute Respiratory Syndrome/prevention & control , Severe Acute Respiratory Syndrome/therapy
15.
Indian J Med Res ; 151(2 & 3): 160-171, 2020.
Article in English | MEDLINE | ID: covidwho-113840

ABSTRACT

The newly emerged 2019 novel coronavirus (CoV), named as severe acute respiratory syndrome CoV-2 (SARS-CoV-2), like SARS-CoV (now, SARS-CoV-1) and Middle East respiratory syndrome CoV (MERS-CoV), has been associated with high infection rates with over 36,405 deaths. In the absence of approved marketed drugs against coronaviruses, the treatment and management of this novel CoV disease (COVID-19) worldwide is a challenge. Drug repurposing that has emerged as an effective drug discovery approach from earlier approved drugs could reduce the time and cost compared to de novo drug discovery. Direct virus-targeted antiviral agents target specific nucleic acid or proteins of the virus while host-based antivirals target either the host innate immune responses or the cellular machineries that are crucial for viral infection. Both the approaches necessarily interfere with viral pathogenesis. Here we summarize the present status of both virus-based and host-based drug repurposing perspectives for coronaviruses in general and the SARS-CoV-2 in particular.


Subject(s)
Coronavirus Infections/drug therapy , Drug Repositioning , Pneumonia, Viral/drug therapy , Antiviral Agents/therapeutic use , Betacoronavirus , Drug Discovery , Humans , Molecular Docking Simulation , Pandemics , Protease Inhibitors/therapeutic use , Viral Proteins/antagonists & inhibitors
16.
ChemMedChem ; 15(11): 907-932, 2020 06 04.
Article in English | MEDLINE | ID: covidwho-108817

ABSTRACT

The COVID-19 pandemic caused by SARS-CoV-2 infection is spreading at an alarming rate and has created an unprecedented health emergency around the globe. There is no effective vaccine or approved drug treatment against COVID-19 and other pathogenic coronaviruses. The development of antiviral agents is an urgent priority. Biochemical events critical to the coronavirus replication cycle provided a number of attractive targets for drug development. These include, spike protein for binding to host cell-surface receptors, proteolytic enzymes that are essential for processing polyproteins into mature viruses, and RNA-dependent RNA polymerase for RNA replication. There has been a lot of ground work for drug discovery and development against these targets. Also, high-throughput screening efforts have led to the identification of diverse lead structures, including natural product-derived molecules. This review highlights past and present drug discovery and medicinal-chemistry approaches against SARS-CoV, MERS-CoV and COVID-19 targets. The review hopes to stimulate further research and will be a useful guide to the development of effective therapies against COVID-19 and other pathogenic coronaviruses.


Subject(s)
Antiviral Agents/therapeutic use , Chemistry, Pharmaceutical/trends , Coronavirus Infections/drug therapy , Drug Development , Pneumonia, Viral/drug therapy , Antiviral Agents/pharmacology , Drug Discovery , Humans , Models, Molecular , Pandemics , Protease Inhibitors/therapeutic use
17.
Mar Drugs ; 18(4)2020 Apr 23.
Article in English | MEDLINE | ID: covidwho-108816

ABSTRACT

The current emergency due to the worldwide spread of the COVID-19 caused by the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a great concern for global public health. Already in the past, the outbreak of severe acute respiratory syndrome (SARS) in 2003 and Middle Eastern respiratory syndrome (MERS) in 2012 demonstrates the potential of coronaviruses to cross-species borders and further underlines the importance of identifying new-targeted drugs. An ideal antiviral agent should target essential proteins involved in the lifecycle of SARS-CoV. Currently, some HIV protease inhibitors (i.e., Lopinavir) are proposed for the treatment of COVID-19, although their effectiveness has not yet been assessed. The main protease (Mpr) provides a highly validated pharmacological target for the discovery and design of inhibitors. We identified potent Mpr inhibitors employing computational techniques that entail the screening of a Marine Natural Product (MNP) library. MNP library was screened by a hyphenated pharmacophore model, and molecular docking approaches. Molecular dynamics and re-docking further confirmed the results obtained by structure-based techniques and allowed this study to highlight some crucial aspects. Seventeen potential SARS-CoV-2 Mpr inhibitors have been identified among the natural substances of marine origin. As these compounds were extensively validated by a consensus approach and by molecular dynamics, the likelihood that at least one of these compounds could be bioactive is excellent.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/enzymology , Coronavirus Infections , Pandemics , Pneumonia, Viral , Protease Inhibitors/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Antiviral Agents/chemistry , Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , Biological Products/chemistry , Biological Products/pharmacology , Biological Products/therapeutic use , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Cysteine Endopeptidases , Databases, Chemical , Humans , Models, Molecular , Molecular Docking Simulation , Pneumonia, Viral/drug therapy , Pneumonia, Viral/virology , Protease Inhibitors/chemistry , Protease Inhibitors/therapeutic use
18.
Pediatr Infect Dis J ; 39(5): 355-368, 2020 05.
Article in English | MEDLINE | ID: covidwho-101831

ABSTRACT

Coronaviruses (CoVs) are a large family of enveloped, single-stranded, zoonotic RNA viruses. Four CoVs commonly circulate among humans: HCoV2-229E, -HKU1, -NL63 and -OC43. However, CoVs can rapidly mutate and recombine leading to novel CoVs that can spread from animals to humans. The novel CoVs severe acute respiratory syndrome coronavirus (SARS-CoV) emerged in 2002 and Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012. The 2019 novel coronavirus (SARS-CoV-2) is currently causing a severe outbreak of disease (termed COVID-19) in China and multiple other countries, threatening to cause a global pandemic. In humans, CoVs mostly cause respiratory and gastrointestinal symptoms. Clinical manifestations range from a common cold to more severe disease such as bronchitis, pneumonia, severe acute respiratory distress syndrome, multi-organ failure and even death. SARS-CoV, MERS-CoV and SARS-CoV-2 seem to less commonly affect children and to cause fewer symptoms and less severe disease in this age group compared with adults, and are associated with much lower case-fatality rates. Preliminary evidence suggests children are just as likely as adults to become infected with SARS-CoV-2 but are less likely to be symptomatic or develop severe symptoms. However, the importance of children in transmitting the virus remains uncertain. Children more often have gastrointestinal symptoms compared with adults. Most children with SARS-CoV present with fever, but this is not the case for the other novel CoVs. Many children affected by MERS-CoV are asymptomatic. The majority of children infected by novel CoVs have a documented household contact, often showing symptoms before them. In contrast, adults more often have a nosocomial exposure. In this review, we summarize epidemiologic, clinical and diagnostic findings, as well as treatment and prevention options for common circulating and novel CoVs infections in humans with a focus on infections in children.


Subject(s)
Coronavirus Infections/epidemiology , Animals , Antibodies, Monoclonal/therapeutic use , Child , Coronavirus Infections/diagnosis , Coronavirus Infections/prevention & control , Coronavirus Infections/therapy , Disease Outbreaks , Humans , Middle East Respiratory Syndrome Coronavirus , Nucleic Acid Synthesis Inhibitors/therapeutic use , Pandemics/prevention & control , Pneumonia, Viral/diagnosis , Pneumonia, Viral/epidemiology , Pneumonia, Viral/prevention & control , Pneumonia, Viral/therapy , Protease Inhibitors/therapeutic use , SARS Virus , Severe Acute Respiratory Syndrome/diagnosis , Severe Acute Respiratory Syndrome/epidemiology , Severe Acute Respiratory Syndrome/prevention & control , Severe Acute Respiratory Syndrome/therapy , Vaccines, DNA/therapeutic use , Viral Vaccines/therapeutic use
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