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1.
Mini Rev Med Chem ; 2021 01 26.
Article in English | MEDLINE | ID: covidwho-1547092

##### ABSTRACT

The article has been withdrawn at the request of the editor of the journal Mini-reviews in Medicinal Chemistry due to incoherent content.Bentham Science apologizes to the readers of the journal for any inconvenience this may have caused.The Bentham Editorial Policy on Article Withdrawal can be found at https://benthamscience.com/editorial-policiesmain.php Bentham Science Disclaimer: It is a condition of publication that manuscripts submitted to this journal have not been published and will not be simultaneously submitted or published elsewhere. Furthermore, any data, illustration, structure or table that has been published elsewhere must be reported, and copyright permission for reproduction must be obtained. Plagiarism is strictly forbidden, and by submitting the article for publication the authors agree that the publishers have the legal right to take appropriate action against the authors, if plagiarism or fabricated information is discovered. By submitting a manuscript, the authors agree that the copyright of their article is transferred to the publishers if and when the article is accepted for publication.

2.
Brief Bioinform ; 22(2): 1338-1345, 2021 03 22.
Article in English | MEDLINE | ID: covidwho-1352115

##### ABSTRACT

SARS-CoV-2 is an intensively investigated virus from the order Nidovirales (Coronaviridae family) that causes COVID-19 disease in humans. Through enormous scientific effort, thousands of viral strains have been sequenced to date, thereby creating a strong background for deep bioinformatics studies of the SARS-CoV-2 genome. In this study, we inspected high-frequency mutations of SARS-CoV-2 and carried out systematic analyses of their overlay with inverted repeat (IR) loci and CpG islands. The main conclusion of our study is that SARS-CoV-2 hot-spot mutations are significantly enriched within both IRs and CpG island loci. This points to their role in genomic instability and may predict further mutational drive of the SARS-CoV-2 genome. Moreover, CpG islands are strongly enriched upstream from viral ORFs and thus could play important roles in transcription and the viral life cycle. We hypothesize that hypermethylation of these loci will decrease the transcription of viral ORFs and could therefore limit the progression of the disease.

##### Subject(s)
COVID-19/virology , CpG Islands , Mutation , SARS-CoV-2/genetics , DNA Methylation , Genome, Viral , Humans , Protein Binding
3.
Brief Bioinform ; 22(2): 1150-1160, 2021 03 22.
Article in English | MEDLINE | ID: covidwho-1352102

##### ABSTRACT

The outbreak caused by the novel coronavirus SARS-CoV-2 has been declared a global health emergency. G-quadruplex structures in genomes have long been considered essential for regulating a number of biological processes in a plethora of organisms. We have analyzed and identified 25 four contiguous GG runs (G2NxG2NyG2NzG2) in the SARS-CoV-2 RNA genome, suggesting putative G-quadruplex-forming sequences (PQSs). Detailed analysis of SARS-CoV-2 PQSs revealed their locations in the open reading frames of ORF1 ab, spike (S), ORF3a, membrane (M) and nucleocapsid (N) genes. Identical PQSs were also found in the other members of the Coronaviridae family. The top-ranked PQSs at positions 13385 and 24268 were confirmed to form RNA G-quadruplex structures in vitro by multiple spectroscopic assays. Furthermore, their direct interactions with viral helicase (nsp13) were determined by microscale thermophoresis. Molecular docking model suggests that nsp13 distorts the G-quadruplex structure by allowing the guanine bases to be flipped away from the guanine quartet planes. Targeting viral helicase and G-quadruplex structure represents an attractive approach for potentially inhibiting the SARS-CoV-2 virus.

##### Subject(s)
COVID-19/virology , G-Quadruplexes , SARS-CoV-2/chemistry , Humans , Molecular Docking Simulation , Open Reading Frames
4.
Front Med (Lausanne) ; 8: 636532, 2021.
Article in English | MEDLINE | ID: covidwho-1344270

##### ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative virus of the coronavirus disease 2019 (COVID-19), has been identified in China in late December 2019. SARS-CoV-2 is an enveloped, positive-sense, single-stranded RNA betacoronavirus of the Coronaviridae family. Coronaviruses have genetic proofreading mechanism that corrects copying mistakes and thus SARS-CoV-2 genetic diversity is extremely low. Despite lower mutation rate of the virus, researchers have detected a total of 12,706 mutations in the SARS-CoV-2 genome, the majority of which were single nucleotide polymorphisms. Sequencing data revealed that the SARS-CoV-2 accumulates two-single nucleotide mutations per month in its genome. Recently, an amino acid aspartate (D) to glycine (G) (D614G) mutation due to an adenine to guanine nucleotide change at position 23,403 at the 614th amino-acid position of the spike protein in the original reference genotype has been identified. The SARS-CoV-2 viruses that carry the spike protein D614G mutation have become dominant variant around the world. The D614G mutation has been found to be associated with 3 other mutations in the spike protein. Clinical and pseudovirus experimental studies have demonstrated that the spike protein D614G mutation alters the virus phenotype. However, the impact of the mutation on the rate of transmission between people, disease severity and the vaccine and therapeutic development remains unclear. Three variants of SARS-CoV-2 have recently been identified. They are B.1.1.7 (UK) variant, B.1.351 (N501Y.V2, South African) variant and B.1.1.28 (Brazilian) variant. Epidemiological data suggest that they have a higher transmissibility than the original variant. There are reports that some vaccines are less efficacious against the B.1.351 variant. This review article discusses the effects of novel mutations in the SARS-CoV-2 genome on transmission, clinical outcomes and vaccine development.

5.
Genes Dis ; 7(4): 491-501, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-1343219

##### ABSTRACT

Since the beginning of the 21st century, several viral outbreaks have threatened humankind and posed a new challenge to the modern healthcare system. The recent outbreak in Wuhan (December 2019), China, represents a beta coronavirus classified as novel Severe Acute Respiratory Syndrome Corona Virus-2 (SARS-CoV-2) which belongs to the Coronaviridae family. Novel SARS-CoV-2 represents a significant similarity with previous coronaviruses such as SARS-CoV in 2002, China and MERS-CoV in 2015, Middle East. However, preliminary research investigations have shown the novel SARS-CoV-2 evolved with several mutations and developed the capacity to cross the species, i.e., animal to human. The initial findings have shown that spike proteins are vital molecules target hACE2 receptor for its attachment and entry into cells. After successful entry virus primarily focuses on respiratory airway cell lines and triggers a massive immune response leading to mucus generation. In severe conditions, the virus is capable of forcing viral pneumonia leading to the collapse of the respiratory system, i.e., COVID19. So far, there is a lack of immunity against the virus in humans. At the same in the absence of therapeutic interventions, many countries experienced high mortality, such as the United States, European countries, i.e., Italy, Spain, France, and the United Kingdom. The vaccine development is underway and experiencing challenges, as many reports demonstrated genetic variations in viral genome and proteins as well. The present study provides a complete comprehensive overview of the novel SARS-CoV-2 outbreak, human transmission, and global spread.

6.
Methods Mol Biol ; 2099: 99-106, 2020.
Article in English | MEDLINE | ID: covidwho-1292548

##### ABSTRACT

Since the emergence of the Middle East respiratory syndrome-coronavirus (MERS-CoV) in 2012, more than 2280 confirmed human infections and 800 associated deaths had been reported to the World Health Organization. MERS-CoV is a single-stranded RNA virus that belongs to the Coronaviridae family. MERS-CoV infection leads to a variety of clinical outcomes in humans ranging from asymptomatic and mild infection to severe acute lung injury and multi-organ failure and death. To study the pathogenesis of MERS-CoV infection and development of medical countermeasures (MCMs) for MERS, a number of genetically modified mouse models have been developed, including various versions of transgenic mice expressing the human DPP4 viral receptor. Tracking and quantifying viral infection, among others, in permissive hosts is a key endpoint for studying MERS pathogenesis and evaluating the efficacy of selected MCMs developed for MERS. In addition to quantifying infectious progeny virus which requires high-containment biosafety level (BSL)-3 laboratory, here we outlined an established real-time quantitative RT-PCR (RT-qPCR)-based procedure to unequivocally quantify MERS-CoV-specific RNAs within the lungs of infected human DPP4 (hDPP4, transgenic (hDPP4 Tg) mice under a standard BSL-2 laboratory.

##### Subject(s)
Coronavirus Infections/virology , Middle East Respiratory Syndrome Coronavirus/genetics , RNA, Viral/analysis , Reverse Transcriptase Polymerase Chain Reaction/methods , Animals , Dipeptidyl Peptidase 4/genetics , Dipeptidyl Peptidase 4/metabolism , Disease Models, Animal , Humans , Lung/virology , Mice , Mice, Transgenic , Middle East Respiratory Syndrome Coronavirus/isolation & purification , Real-Time Polymerase Chain Reaction , Receptors, Virus/genetics , Receptors, Virus/metabolism
7.
Brief Bioinform ; 22(6)2021 11 05.
Article in English | MEDLINE | ID: covidwho-1276146

##### ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a causative agent of the coronavirus disease (COVID-19), is a part of the $\beta$-Coronaviridae family. The virus contains five major protein classes viz., four structural proteins [nucleocapsid (N), membrane (M), envelop (E) and spike glycoprotein (S)] and replicase polyproteins (R), synthesized as two polyproteins (ORF1a and ORF1ab). Due to the severity of the pandemic, most of the SARS-CoV-2-related research are focused on finding therapeutic solutions. However, studies on the sequences and structure space throughout the evolutionary time frame of viral proteins are limited. Besides, the structural malleability of viral proteins can be directly or indirectly associated with the dysfunctionality of the host cell proteins. This dysfunctionality may lead to comorbidities during the infection and may continue at the post-infection stage. In this regard, we conduct the evolutionary sequence-structure analysis of the viral proteins to evaluate their malleability. Subsequently, intrinsic disorder propensities of these viral proteins have been studied to confirm that the short intrinsically disordered regions play an important role in enhancing the likelihood of the host proteins interacting with the viral proteins. These interactions may result in molecular dysfunctionality, finally leading to different diseases. Based on the host cell proteins, the diseases are divided in two distinct classes: (i) proteins, directly associated with the set of diseases while showing similar activities, and (ii) cytokine storm-mediated pro-inflammation (e.g. acute respiratory distress syndrome, malignancies) and neuroinflammation (e.g. neurodegenerative and neuropsychiatric diseases). Finally, the study unveils that males and postmenopausal females can be more vulnerable to SARS-CoV-2 infection due to the androgen-mediated protein transmembrane serine protease 2.

##### Subject(s)
COVID-19/genetics , Genome, Viral/genetics , Protein Conformation , SARS-CoV-2/ultrastructure , COVID-19/virology , Coronavirus Envelope Proteins/genetics , Coronavirus Envelope Proteins/ultrastructure , Humans , Membrane Proteins/genetics , Membrane Proteins/ultrastructure , Nucleocapsid Proteins/genetics , Nucleocapsid Proteins/ultrastructure , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/ultrastructure , Viral Replicase Complex Proteins/genetics , Viral Replicase Complex Proteins/ultrastructure , Viral Structural Proteins/genetics , Viral Structural Proteins/ultrastructure
8.
Acta Virol ; 65(2): 107-114, 2021.
Article in English | MEDLINE | ID: covidwho-1271016

##### ABSTRACT

Coronavirus disease 2019 (COVID-19) has turned out as one of the worst medical and economic misfortunes across the globe. The etiological agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a member of the Coronaviridae family and represents a disease manifestation from asymptomatic to severe respiratory damage. High transmissibility and contagious nature of the virus helps it to flourish in a large population. The immune system aids to retain the virus, but with accelerated cytokine secretion, it could transform into double edge sword resulting in unrestrained systemic inflammation which might become life-threatening. SARS-CoV-2 sets substantial impact on T-lymphocytes during its course of infection. The number of CD4+ T, CD8+ T, and Treg cells tend to decrease profoundly in case of severe illness. Besides, the virus modulates the CD4+ T/ CD8+ T and Treg/Th17 cells ratio and induces the functional exhaustion of T cells to make them inefficient. T cells define the pathogenesis of severe cases and provide major contributions in antiviral defense. Therefore, the apprehension of T-lymphocytes in SARS-CoV-2 infection would implicate in developing antivirals, disease control, and would broaden the way for vaccine formulation. Thus, the review depicts the significance of T-lymphocytes interaction with SARS-CoV-2. Keywords: SARS-CoV-2; COVID-19; T-lymphocytes; cytokine; inflammation; immune response.

##### Subject(s)
COVID-19 , SARS-CoV-2 , Antiviral Agents/therapeutic use , CD4-Positive T-Lymphocytes , CD8-Positive T-Lymphocytes , Cytokines/genetics , Humans , T-Lymphocytes
9.
Front Oncol ; 10: 572329, 2020.
Article in English | MEDLINE | ID: covidwho-1264350

##### ABSTRACT

The recent outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or coronavirus disease 2019 (COVID-19) in China, which spread to the rest of the world, led the World Health Organization to classify it as a global pandemic. COVID-19 belongs to the Bettacoronavirus genus of the Coronaviridae family, and it mainly spreads through the respiratory tract. Studies have now confirmed a human-to-human transmission as the primary pathway of spread. COVID-19 patients with a history of diseases such as respiratory system diseases, immune deficiency, diabetes, cardiovascular disease, and cancer are prone to adverse events (admission to the intensive care unit requiring invasive ventilation or even death). The current focus has been on the development of novel therapeutics, including antivirals, monoclonal antibodies, and vaccines. However, although there is undoubtedly an urgent need to identify effective treatment options against infection with COVID-19, it is equally important to clarify management protocols for the other significant diseases from which these patients may suffer, including cancer. This review summarizes the current evidence regarding the epidemiology, pathogenesis, and management of patients with COVID-19. It also aims to provide the reader with insights into COVID-19 in pregnant patients and those with cancer, outlining necessary precautions relevant to cancer patients. Finally, we provide the available evidence on the latest potent antiviral drugs and vaccines of COVID-19 and the ongoing drug trials.

10.
Bull Acad Natl Med ; 205(7): 732-736, 2021 Aug.
Article in French | MEDLINE | ID: covidwho-1252480

##### ABSTRACT

From the beginning of this century, three coronaviruses (CoVs) have caused severe human respiratory diseases, including severe respiratory syndrome (SARS), Middle East respiratory syndrome (MERS) and corona virus disease 2019 (COVID-19), which outbroke in 2002-2003, 2012 and 2019-2020, respectively. These viruses are three different species belonging to Coronaviridae family, Betacoronavirus genus. Discovery of closely-related CoVs in bats indicates that bats are natural reservoirs of these viruses. How and when the bat CoVs cross-species barriers to infect humans are largely understudied. This article provides an overview of the distribution, genetic evolution and interspecies transmission of bat coronaviruses in China, particularly focusing on bat SARS-related CoVs (SARSr-CoVs). Our studies showed that SARS-related CoVs are highly prevalent in horseshoe bats and some of them use the same receptor as SARS-CoV and SARS-CoV-2 and have wide cell tissue tropism. However, these bat viruses seem to be low pathogenic in human ACE2 transgenic mice compared with the SARS-CoV-2. These results imply that these bat CoVs have potential interspecies transmission to other animals and humans. Our work highlights the necessity of preparedness for future emerging infectious diseases caused by these CoVs.

11.
Chem Biol Drug Des ; 98(2): 207-211, 2021 08.
Article in English | MEDLINE | ID: covidwho-1247143

##### ABSTRACT

The full-length human ACE2 in complex with B0 AT1 is anchored to two S in open pre-fusion state which allows establishing pre-invasion interactions with the ACE2 N-terminal domain.

##### Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/virology , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Amino Acid Sequence , Binding Sites , Humans , Molecular Dynamics Simulation , Protein Binding , Protein Domains , Sequence Homology, Amino Acid
12.
Wien Klin Wochenschr ; 133(17-18): 966-972, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1245637

##### ABSTRACT

A variety of pneumonia cases of unknown cause emerged in China in December 2019. A new virus belonging to the Coronaviridae family, called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19). Within a few days, COVID-19 became a pandemic disease. This review aimed to investigate the possible implications of COVID-19 for human reproductive systems, as in previous studies ACE2 was highly expressed in some organs of these systems, such as the testicles. A total of 41 publications were found in the specialized databases and, after selection, 7 articles were used to build this study. Our results showed that the fever caused by COVID-19 has a negative effect on spermatogenesis, there is high expression of ACE2 in the testicles and in the uterine tubes and there is a higher level of transmembrane protease serine 2 (TMPRSS2), which is also responsible for the entry of the virus into the cell. Moreover, it was noted that there was viral genetic material in the semen and an increase in the serum concentration of luteinizing hormone (LH) in men and women, which could cause hypogonadism. Thus, we conclude that there is the possibility of infection and malfunction in the reproductive organs as well as the plausibility of sexual transmission of this disease. Further analysis must be carried out to prove the effects of COVID-19 on the human reproductive systems.

##### Subject(s)
COVID-19 , Female , Genitalia, Female , Humans , Male , Pandemics , SARS-CoV-2 , Semen
13.
Front Pharmacol ; 12: 653064, 2021.
Article in English | MEDLINE | ID: covidwho-1245288

##### ABSTRACT

Porcine epidemic diarrhea virus (PEDV), a member of the Coronaviridae family has become increasingly probelmatic in the pig farming industry. Currently, there are no effective, globally applicable vaccines against PEDV. Here, we tested a recombinant PEDV vaccine candidate based on the expression of the core neutralising epitope (COE) of PEDV conjugated to polymeric immunoglobulin G scaffold (PIGS) in glycoengineered Nicotiana be nthamiana plants. The biological activity of COE-PIGS was demonstrated by binding to C1q component of the complement system, as well as the surface of antigen-presenting cells (APCs) in vitro. The recombinant COE-PIGS induced humoral and cellular immune responses specific for PEDV after both systemic and mucosal vaccination. Altogether, the data indicated that PEDV antigen fusion to poly-Fc could be a promising vaccine platform against respiratory PEDV infection.

14.
Int J Mol Sci ; 22(11)2021 May 21.
Article in English | MEDLINE | ID: covidwho-1244038

##### ABSTRACT

In late 2019, a new member of the Coronaviridae family, officially designated as "severe acute respiratory syndrome coronavirus 2" (SARS-CoV-2), emerged and spread rapidly. The Coronavirus Disease-19 (COVID-19) outbreak was accompanied by a high rate of morbidity and mortality worldwide and was declared a pandemic by the World Health Organization in March 2020. Within the Coronaviridae family, SARS-CoV-2 is considered to be the third most highly pathogenic virus that infects humans, following the severe acute respiratory syndrome coronavirus (SARS-CoV) and the Middle East respiratory syndrome coronavirus (MERS-CoV). Four major mechanisms are thought to be involved in COVID-19 pathogenesis, including the activation of the renin-angiotensin system (RAS) signaling pathway, oxidative stress and cell death, cytokine storm, and endothelial dysfunction. Following virus entry and RAS activation, acute respiratory distress syndrome develops with an oxidative/nitrosative burst. The DNA damage induced by oxidative stress activates poly ADP-ribose polymerase-1 (PARP-1), viral macrodomain of non-structural protein 3, poly (ADP-ribose) glycohydrolase (PARG), and transient receptor potential melastatin type 2 (TRPM2) channel in a sequential manner which results in cell apoptosis or necrosis. In this review, blockers of angiotensin II receptor and/or PARP, PARG, and TRPM2, including vitamin D3, trehalose, tannins, flufenamic and mefenamic acid, and losartan, have been investigated for inhibiting RAS activation and quenching oxidative burst. Moreover, the application of organic and inorganic nanoparticles, including liposomes, dendrimers, quantum dots, and iron oxides, as therapeutic agents for SARS-CoV-2 were fully reviewed. In the present review, the clinical manifestations of COVID-19 are explained by focusing on molecular mechanisms. Potential therapeutic targets, including the RAS signaling pathway, PARP, PARG, and TRPM2, are also discussed in depth.

##### Subject(s)
COVID-19/drug therapy , COVID-19/therapy , Cytokine Release Syndrome/drug therapy , Nanomedicine/methods , Oxidative Stress/drug effects , Poly (ADP-Ribose) Polymerase-1/metabolism , SARS-CoV-2/drug effects , Apoptosis/drug effects , COVID-19/metabolism , COVID-19/physiopathology , Cholecalciferol/pharmacology , GTPase-Activating Proteins/antagonists & inhibitors , GTPase-Activating Proteins/metabolism , Humans , Poly (ADP-Ribose) Polymerase-1/antagonists & inhibitors , Renin-Angiotensin System/drug effects , SARS-CoV-2/growth & development , SARS-CoV-2/metabolism , TRPM Cation Channels/antagonists & inhibitors , TRPM Cation Channels/metabolism , Tannins/pharmacology , Trehalose/pharmacology
15.
Scand J Clin Lab Invest ; 81(4): 255-263, 2021 07.
Article in English | MEDLINE | ID: covidwho-1242057

##### ABSTRACT

Coronaviruses belonging to the Coronaviridae family are single-stranded RNA viruses. The entry of SARS-CoV-2 is accomplished via ACE-2 receptors. SARS-CoV-2 infection coactivates both innate and adaptive immune responses. Although SARS-CoV-2 stimulates antibody production with a typical pattern of IgM/IgG, cellular immunity is also impaired. In severe cases, low CD4 + and CD8 + T cell counts are associated with impaired immune functions, and high neutrophil/lymphocyte ratios accompanying low lymphocyte subsets have been demonstrated. Recently, high IFN -α/Î³ ratios with impaired T cell responses, and increased IL-1, IL-6, TNF-α, MCP-1, IP-10, IL-4, IL-10 have been reported in COVID-19 infection. Increased proinflammatory cytokines and chemokines in patients with severe COVID-19 may cause the suppression of CD4 + and CD8 + T cells and regulatory T cells, causing excessive inflammatory responses and fatal cytokine storm with tissue and organ damage. Consequently, novel therapeutics to be developed against host immune system, including blockade of cytokines (IL-6, IL-1, IFN) themselves, their receptors or signaling pathways- JAK inhibitors- could be effective as potential therapeutics.

##### Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , COVID-19/immunology , COVID-19/physiopathology , Adrenal Cortex Hormones/therapeutic use , Animals , Antiviral Agents/therapeutic use , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/virology , Cytokines/antagonists & inhibitors , Cytokines/metabolism , Glucocorticoids/therapeutic use , Humans , Hydroxychloroquine/therapeutic use , Immunotherapy/methods , Macrophages/immunology , Macrophages/pathology , Macrophages/virology
16.
Comput Struct Biotechnol J ; 19: 3133-3148, 2021.
Article in English | MEDLINE | ID: covidwho-1240273

##### ABSTRACT

The world is facing the COVID-19 pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Likewise, other viruses of the Coronaviridae family were responsible for causing epidemics earlier. To tackle these viruses, there is a lack of approved antiviral drugs. Therefore, we have developed robust computational methods to predict the repurposed drugs using machine learning techniques namely Support Vector Machine, Random Forest, k-Nearest Neighbour, Artificial Neural Network, and Deep Learning. We used the experimentally validated drugs/chemicals with anticorona activity (IC50/EC50) from 'DrugRepV' repository. The unique entries of SARS-CoV-2 (142), SARS (221), MERS (123), and overall Coronaviruses (414) were subdivided into the training/testing and independent validation datasets, followed by the extraction of chemical/structural descriptors and fingerprints (17968). The highly relevant features were filtered using the recursive feature selection algorithm. The selected chemical descriptors were used to develop prediction models with Pearson's correlation coefficients ranging from 0.60 to 0.90 on training/testing. The robustness of the predictive models was further ensured using external independent validation datasets, decoy datasets, applicability domain, and chemical analyses. The developed models were used to predict promising repurposed drug candidates against coronaviruses after scanning the DrugBank. Top predicted molecules for SARS-CoV-2 were further validated by molecular docking against the spike protein complex with ACE receptor. We found potential repurposed drugs namely Verteporfin, Alatrofloxacin, Metergoline, Rescinnamine, Leuprolide, and Telotristat ethyl with high binding affinity. These 'anticorona' computational models would assist in antiviral drug discovery against SARS-CoV-2 and other Coronaviruses.

17.
Evid Based Complement Alternat Med ; 2021: 6632623, 2021.
Article in English | MEDLINE | ID: covidwho-1238611

##### ABSTRACT

Since its inception, the coronavirus disease 2019 (COVID-19) pandemic has infected millions of people around the world. Therefore, it is necessary to find effective treatments against Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), as it is the viral source of COVID-19. Alkaloids are one of the most widespread plant-derived natural compounds with prominent antiviral effects. Accordingly, these phytochemicals have been promising candidates towards discovering effective treatments for COVID-19. Alkaloids have shown potential anti-SARS-CoV activities via inhibiting pathogenesis-associated targets of the Coronaviridae family that are required for the virus life cycle. In the current study, the chemistry, plant sources, and antiviral effects of alkaloids, as well as their anti-SARS-CoV-2 effect with related mechanisms, are reviewed towards discovering an effective treatment against COVID-19.

18.
Ann Clin Microbiol Antimicrob ; 20(1): 35, 2021 May 18.
Article in English | MEDLINE | ID: covidwho-1234561

##### ABSTRACT

Coronavirus disease 2019 (COVID-19) is the second pandemic of the twenty-first century, with over one-hundred million infections and over two million deaths to date. It is a novel strain from the Coronaviridae family, named Severe Acute Respiratory Distress Syndrome Coronavirus-2 (SARS-CoV-2); the 7th known member of the coronavirus family to cause disease in humans, notably following the Middle East Respiratory syndrome (MERS), and Severe Acute Respiratory Distress Syndrome (SARS). The most characteristic feature of this single-stranded RNA molecule includes the spike glycoprotein on its surface. Most patients with COVID-19, of which the elderly and immunocompromised are most at risk, complain of flu-like symptoms, including dry cough and headache. The most common complications include pneumonia, acute respiratory distress syndrome, septic shock, and cardiovascular manifestations. Transmission of SARS-CoV-2 is mainly via respiratory droplets, either directly from the air when an infected patient coughs or sneezes, or in the form of fomites on surfaces. Maintaining hand-hygiene, social distancing, and personal protective equipment (i.e., masks) remain the most effective precautions. Patient management includes supportive care and anticoagulative measures, with a focus on maintaining respiratory function. Therapy with dexamethasone, remdesivir, and tocilizumab appear to be most promising to date, with hydroxychloroquine, lopinavir, ritonavir, and interferons falling out of favour. Additionally, accelerated vaccination efforts have taken place internationally, with several promising vaccinations being mass deployed. In response to the COVID-19 pandemic, countries and stakeholders have taken varying precautions to combat and contain the spread of the virus and dampen its collateral economic damage. This review paper aims to synthesize the impact of the virus on a global, micro to macro scale.

##### Subject(s)
COVID-19/epidemiology , Global Health , SARS-CoV-2 , COVID-19/prevention & control , COVID-19/therapy , COVID-19/transmission , COVID-19 Vaccines/immunology , Humans , Risk Factors , SARS-CoV-2/pathogenicity , Virulence
19.
Proteins ; 89(10): 1289-1299, 2021 10.
Article in English | MEDLINE | ID: covidwho-1233229

##### ABSTRACT

A novel virus, severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2), causing coronavirus disease 2019 (COVID-19) worldwide appeared in 2019. Detailed scientific knowledge of the members of the Coronaviridae family, including the Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is currently lacking. Structural studies of the MERS-CoV proteins in the current literature are extremely limited. We present here detailed characterization of the structural properties of MERS-CoV macro domain in aqueous solution. Additionally, we studied the impacts of chosen force field parameters and parallel tempering simulation techniques on the predicted structural properties of MERS-CoV macro domain in aqueous solution. For this purpose, we conducted extensive Hamiltonian-replica exchange molecular dynamics simulations and Temperature-replica exchange molecular dynamics simulations using the CHARMM36m and AMBER99SB parameters for the macro domain. This study shows that the predicted secondary structure properties including their propensities depend on the chosen simulation technique and force field parameter. We perform structural clustering based on the radius of gyration and end-to-end distance of MERS-CoV macro domain in aqueous solution. We also report and analyze the residue-level intrinsic disorder features, flexibility and secondary structure. Furthermore, we study the propensities of this macro domain for protein-protein interactions and for the RNA and DNA binding. Overall, results are in agreement with available nuclear magnetic resonance spectroscopy findings and present more detailed insights into the structural properties of MERS CoV macro domain in aqueous solution. All in all, we present the structural properties of the aqueous MERS-CoV macro domain using different parallel tempering simulation techniques, force field parameters and bioinformatics tools.

##### Subject(s)
Middle East Respiratory Syndrome Coronavirus/chemistry , Middle East Respiratory Syndrome Coronavirus/metabolism , Molecular Dynamics Simulation , Water/chemistry , Water/metabolism , Humans , Protein Domains/physiology , Protein Structure, Secondary , Solutions
20.
Comput Biol Med ; 134: 104471, 2021 07.
Article in English | MEDLINE | ID: covidwho-1231980

##### ABSTRACT

SARS-COV-2, Severe Acute Respiratory Syndrome (SARS), and the Middle East respiratory syndrome-related coronavirus (MERS) viruses are from the coronaviridae family; the former became a global pandemic (with low mortality rate) while the latter were confined to a limited region (with high mortality rates). To investigate the possible structural differences at basic levels for the three viruses, genomic and proteomic sequences were downloaded and converted to polynomial datasets. Seven attribute weighting (feature selection) models were employed to find the key differences in their genome's nucleotide sequence. Most attribute weighting models selected the final nucleotide sequences (from 29,000th nucleotide positions to the end of the genome) as significantly different among the three virus classes. The genome and proteome sequences of this hot zone area (which corresponds to the 3'UTR region and encodes for nucleoprotein (N)) and Spike (S) protein sequences (as the most important viral protein) were converted into binary images and were analyzed by image processing techniques and Convolutional deep Neural Network (CNN). Although the predictive accuracy of CNN for Spike (S) proteins was low (0.48%), the machine-based learning algorithms were able to classify the three members of coronaviridae viruses with 100% accuracy based on 3'UTR region. For the first time ever, the relationship between the possible structural differences of coronaviruses at the sequential levels and their pathogenesis are being reported, which paves the road to deciphering the high pathogenicity of the SARS-COV-2 virus.

##### Subject(s)
COVID-19 , Middle East Respiratory Syndrome Coronavirus , Humans , Middle East Respiratory Syndrome Coronavirus/genetics , Pandemics , Proteomics , SARS-CoV-2
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