Chemoinformatics and bioinformatics by discrete mathematics and numbers: an adventure from small data to the realm of emerging big data

Currently, we are witnessing the emergence of big data in various fields including the biomedical and natural sciences. The size of chemoinformatics and bioinformatics databases is increasing every day. This gives us both challenges and opportunities. This chapter discusses the mathematical methods used in these fields both for the generation and analysis of such data. It is emphasized that proper use of robust statistical and machine learning methods in the analysis of the available big data may facilitate both hypothesis-driven and discovery-oriented research. © 2023 Elsevier Inc. All rights reserved.

Antiviral Effects of Asian Natural Products Targeting SARS, MERS, and COVID-19

Viral diseases initiated by Coronavirus (CoV) have become the major public health problems worldwide in the last two decades. The recent emergence of the deadly COVID-19 due to SARS-CoV-2 has created unprecedented pandemic situations around the globe making the need for antiviral molecules to treat it. Encountering the health conditions of the patients with synthetic molecules has shown some unpredictable results, including side effects. To face this complex situa-tion, natural products can be good sources of enormous treatment options with fewer side effects. Wide diversity, easy availability, and a good number of scientific researches on Asian origin natural products can be a great tool to meet this critical situation. This paper reviews the currently available Asian natural products with potential antiviral effects on CoV. It includes the potential natural products of whole plant extract, partial plant extract, isolated pure compounds, and isolated pure set of compounds. Besides, the available information of in vitro and in silico from very recent pa-pers are also summarized for the ease of future research. As a rapid search for a potential anti-CoV therapy is undergoing, Asian natural products will provide promising results but still, there are many challenges in front of us, including the robust in vitro assay to confirm the antiviral property, toxicity analysis, and fulfillment of regulatory needs. The use of appropriate natural products with the potential for a safe and more effective anti-CoV property requires multidisciplinary research with preclinical and clinical researchers, which will improve their clinical applications.Copyright © 2021 Bentham Science Publishers.

Applications of alignment-free sequence descriptors in the characterization of sequences in the age of big data: a case study with Zika virus, SARS, MERS, and COVID-19

This chapter gives a detailed presentation of the theoretical background and computational approaches to the utility of alignment-free sequence descriptors and multidimensional variable reduction methods in the characterization and visualization of biological sequence data. The utility of such novel methods developed by the authors of this chapter is shown using data on case studies of severe acute respiratory syndrome, Middle East respiratory syndrome, Coronavirus disease-2019, and Zika viruses. © 2023 Elsevier Inc. All rights reserved.

Single Amino Acid Substitution in the Receptor Binding Domain of Spike Protein Is Sufficient To Convert the Neutralization Profile between Ethiopian and Middle Eastern Isolates of Middle East Respiratory Coronavirus.

Middle East respiratory syndrome coronavirus (MERS-CoV) is a zoonotic virus that causes MERS, which is endemic in the Middle East. The absence of human cases in Africa despite the presence of MERS-CoV suggests virological differences between MERS-CoVs in Africa and the Middle East. In fact, in the laboratory, recombinant MERS-CoV carrying the spike (S) protein of Ethiopian isolates exhibits attenuated properties, being more easily neutralized and replicating slower than viruses carrying the S protein of Middle Eastern isolate, EMC. In this study, to identify the amino acids that define the different virological features between Ethiopian and Middle Eastern MERS-CoVs, neutralization titers and viral replication were evaluated using recombinant MERS-CoVs carrying amino acid substitution(s) in the S protein. A single amino acid difference introduced into the receptor binding domain was sufficient to reverse the difference in the neutralizing properties of the S protein between Ethiopian and Middle Eastern MERS-CoVs. Furthermore, amino acid mutations in the S1 and S2 regions of S protein were collectively involved in slow viral replication. Since even a single amino acid difference in S protein can reverse the viral properties of MERS-CoV, it should be noted that multiple mutations may induce a significant change. Careful monitoring of genetic alterations in MERS-CoVs in Africa is therefore required to detect the emergence of virulent strains generated by a few genetic differences. IMPORTANCE There have been no reported cases of human Middle East respiratory syndrome (MERS) in Africa, despite the presence of MERS coronavirus (MERS-CoV). Previous studies have shown that recombinant MERS-CoV carrying the S protein of an Ethiopian isolate replicated slower and was more easily neutralized relative to MERS-CoV carrying the S protein of a Middle Eastern isolate. In this study, we investigated the amino acid(s) in S protein associated with the different viral characteristics between Ethiopian and Middle Eastern MERS-CoVs. The results revealed that a single amino acid difference in the receptor binding domain was sufficient to reverse the neutralization profile. This implies that slight genetic changes can alter the predominant population of MERS-CoV, similar to the transition of variants of severe acute respiratory syndrome coronavirus-2. Careful genetic monitoring of isolates is important to detect the spread of possible virulent MERS-CoVs generated by mutation(s).

Human Coronavirus Infections—Severe Acute Respiratory Syndrome (SARS), Middle East Respiratory Syndrome (MERS), and SARS-CoV-2

Three novel coronaviruses have emerged as new lethal zoonotic pathogens of humans during the past 17 years: The Severe Acute Respiratory Syndrome (SARS) coronavirus (SARS-CoV), the Middle East Respiratory Syndrome (MERS) coronavirus (MERS-CoV), and most recently SARS-CoV-2. SARS-CoV first surfaced as a human pathogen in Guangdong, China in November 2002 and rapidly spread worldwide with 8098 cases and 774 deaths before the end of the epidemic. SARS-like CoVs have been detected in horseshoe bats with high sequence homology with human or civet isolates, suggesting that bats could be a natural reservoir of a close ancestor of SARS-CoV. No cases of SARS have been reported since January 2004. MERS-CoV was first reported in September 2012, after it was isolated from respiratory samples from a patient in Jeddah, Saudi Arabia who died in June 2012. How humans acquire MERS-CoV infection is not yet known although bats and dromedary camels are intermediary reservoirs. MERS-CoV continues to circulate in the Middle East. As of May 22, 2019, 2428 cases of laboratory-confirmed MERS-CoV cases reported to the World Health Organization, including 838 deaths (34.5% mortality) have been reported from 27 countries. While the majority of MERS cases occur in the Middle East, travel related MERS cases have been reported from all continents. Large health care associated outbreaks of MERS-CoV have occurred in Saudi Arabia, United Arab Emirates, and the Republic of Korea. SARS-CoV-2 emerged from Wuhan, China in December 2019, and by March 2020 had established as a pandemic which has caused massive disruption in multiple countries. The eventual mortality caused by this virus remains to be seen. All three viruses cause a similar wide range of nonspecific clinical manifestations from mild upper respiratory tract illness to severe respiratory, gastrointestinal and other extra-pulmonary disease. Early recognition of cases, improved compliance with internationally recommended infection control protocols, and rapid implementation of infection control measures are required to prevent health care facility-associated outbreaks, and in the case of SARS-CoV-2 for control of community spread as well. Treatment is supportive and there are no specific antivirals or vaccines available for both SARS and MERS. © 2022 Elsevier Ltd. All rights reserved

COVID-19 Pathogen Viral Evolution Leading to Increased Infectivity.

Objective This study investigated changes in viral protein structures within the receptor-binding domains (RBDs) of the viral particles of severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), that may explain the evolution of increased infectivity. Background The emergence of severely pathogenic Betacoronaviruses indicates increased infectivity and host range, possibly related to the evolution of the viral genome and subsequent proteins, specifically coronavirus spike proteins that are involved in host receptor binding and cell entry. Methods Amino acid sequences of the spike protein of each virus (SARS-CoV, MERS-CoV, and SARS-CoV-2) were obtained from the NCBI Virus Database, along with the sequences for their known receptors, and analyzed for sequence changes and peptide properties to determine the characteristics of the virus-receptor binding. Crystal structures were retrieved from the Protein Database for each virus and receptor and visualized using proteomic analysis software (PyMOL 2.1) (Schrödinger, Inc., New York, USA). Results SARS-CoV-2 displayed the largest magnitude difference (+32.4) in net charge between the virus and its receptor, angiotensin-converting enzyme 2 (ACE2), suggesting stronger electrostatic binding. SARS-CoV-2 also had the largest RBD (7140.29 Å2), indicating more surface area for interaction with the ACE2 receptor. Conclusion The evolution of SARS-CoV-2 for a larger and more electrostatically "sticky" RBD compared to other pathogenic Betacoronaviruses may contribute to observations of SARS-CoV-2 having a stronger or more stable binding, leading to increased transmissibility and infectivity. Further investigation of conserved genomic regions between these viruses may facilitate the development of viable vaccines and treatments.

Immunogenic Epitope-Based Vaccine Prediction from Surface Glycoprotein of MERS-CoV by Deploying Immunoinformatics Approach.

Middle East respiratory syndrome coronavirus (MERS-CoV) has caused a high mortality rate since its emergence in 2012 in the Middle East. Currently, no effective drug or vaccine is available for MERS-CoV. Supportive care and prevention are the only ways to manage infection. In this study, we identified an epitope-based vaccine that could be an optimal solution for the prevention of MERS-CoV infection. By deploying an immunoinformatics approach, we predicted a subunit vaccine based on the surface glycoprotein (S protein) of MERS-CoV. For this purpose, the proteome of the MERS-CoV spike protein was obtained from the NCBI GenBank database. Then, it was subjected to a check for allergenicity using the Allergen FP v.1.0 tool. The Vaxijen v.2.0 tool was used to conduct antigenicity tests for binding with major histocompatibility complex class I and II molecules. The solidity of the predicted epitope-allele docked complex was evaluated by a molecular dynamics simulation. After docking a total of eight epitopes from the MERS-CoV S protein, further analyses predicted their non-toxicity and therapeutic immunogenic properties. These epitopes have potential utility as vaccine candidates against MERS-CoV, to be validated by wet-lab testing. Supplementary Information: The online version contains supplementary material available at 10.1007/s10989-022-10382-5.

Discovery of Highly Potent Fusion Inhibitors with Potential Pan-Coronavirus Activity That Effectively Inhibit Major COVID-19 Variants of Concern (VOCs) in Pseudovirus-Based Assays.

We report the discovery of several highly potent small molecules with low-nM potency against severe acute respiratory syndrome coronavirus (SARS-CoV; lowest half-maximal inhibitory concentration (IC50: 13 nM), SARS-CoV-2 (IC50: 23 nM), and Middle East respiratory syndrome coronavirus (MERS-CoV; IC50: 76 nM) in pseudovirus-based assays with excellent selectivity index (SI) values (>5000), demonstrating potential pan-coronavirus inhibitory activities. Some compounds showed 100% inhibition against the cytopathic effects (CPE; IC100) of an authentic SARS-CoV-2 (US_WA-1/2020) variant at 1.25 µM. The most active inhibitors also potently inhibited variants of concern (VOCs), including the UK (B.1.1.7) and South African (B.1.351) variants and the Delta variant (B.1.617.2) originally identified in India in pseudovirus-based assay. Surface plasmon resonance (SPR) analysis with one potent inhibitor confirmed that it binds to the prefusion SARS-CoV-2 spike protein trimer. These small-molecule inhibitors prevented virus-mediated cell-cell fusion. The absorption, distribution, metabolism, and excretion (ADME) data for one of the most active inhibitors, NBCoV1, demonstrated drug-like properties. An in vivo pharmacokinetics (PK) study of NBCoV1 in rats demonstrated an excellent half-life (t1/2) of 11.3 h, a mean resident time (MRT) of 14.2 h, and oral bioavailability. We expect these lead inhibitors to facilitate the further development of preclinical and clinical candidates.

Assessment of COVID-19 Treatment Advised in Different Ethnic Populations.

A virus is an infectious agent that can only replicate within a host organism and can infect a variety of living organisms, including bacteria, plants, and animals. Viruses are so small that a microscope is necessary to visualize them, and they have a very simple structure. A coronavirus is a group of viruses that can cause diseases, for instance, the basic cold, severe acute respiratory syndrome (SARS), and the Middle East respiratory syndrome (MERS). The patients affected with the COVID-19 infection will encounter respiratory sickness and can recuperate without requiring normal therapy. Individuals with clinical issues like cardiovascular problems, diabetes, and respiratory illness will suffer from the ailment. COVID-19 disease spreads through aerosols or the nose when an infected individual hacks or sneezes. In 2019, a new disease, known as novel coronavirus disease 2019 (COVID-19), was discovered in China, and on March 11, 2020, it was declared a pandemic disease by the World Health Organization (WHO), spreading rapidly across 194 countries in Europe, North America, Asia, the Middle East, Latin America, and Africa. The best way to stop the spread of the transmission is to be instructed about COVID-19 and how it spreads. In this survey, we are endeavoring to focus on the drugs and vaccines that are used for the treatment and prevention of COVID-19.

Evaluating MERS-CoV Entry Pathways.

Middle East respiratory syndrome coronavirus (MERS-CoV) is an emerging zoonotic pathogen with a broad host range. The extent of MERS-CoV in nature can be traced to its adaptable cell entry steps. The virus can bind host-cell carbohydrates as well as proteinaceous receptors. Following receptor interaction, the virus can utilize diverse host proteases for cleavage activation of virus-host cell membrane fusion and subsequent genome delivery. The fusion and genome delivery steps can be completed at variable times and places, either at or near cell surfaces or deep within endosomes. Investigators focusing on the CoVs have developed several methodologies that effectively distinguish these different cell entry pathways. Here we describe these methods, highlighting virus-cell entry factors, entry inhibitors, and viral determinants that specify the cell entry routes. While the specific methods described herein were utilized to reveal MERS-CoV entry pathways, they are equally suited for other CoVs, as well as other protease-dependent viral species.

Plants and Natural Products with Activity against Various Types of Coronaviruses: A Review with Focus on SARS-CoV-2.

COVID-19 is a pandemic disease caused by the SARS-CoV-2 virus, which is potentially fatal for vulnerable individuals. Disease management represents a challenge for many countries, given the shortage of medicines and hospital resources. The objective of this work was to review the medicinal plants, foods and natural products showing scientific evidence for host protection against various types of coronaviruses, with a focus on SARS-CoV-2. Natural products that mitigate the symptoms caused by various coronaviruses are also presented. Particular attention was placed on natural products that stabilize the Renin-Angiotensin-Aldosterone System (RAAS), which has been associated with the entry of the SARS-CoV-2 into human cells.

Biochemical Characterization of Middle East Respiratory Syndrome Coronavirus Spike Protein Proteolytic Processing.

The coronavirus spike envelope glycoprotein is an essential viral component that mediates virus entry events. Biochemical assessment of the spike protein is critical for understanding structure-function relationships and the roles of the protein in the viral life cycle. Coronavirus spike proteins are typically proteolytically processed and activated by host cell enzymes such as trypsin-like proteases, cathepsins, or proprotein-convertases. Analysis of coronavirus spike proteins by western blot allows the visualization and assessment of proteolytic processing by endogenous or exogenous proteases. Here, we present a method based on western blot analysis to investigate spike protein proteolytic cleavage by transient transfection of HEK-293 T cells allowing expression of the spike protein of the highly pathogenic Middle East respiratory syndrome coronavirus in the presence or absence of a cellular trypsin-like transmembrane serine protease, matriptase. Such analysis enables the characterization of cleavage patterns produced by a host protease on a coronavirus spike glycoprotein.

Preclinical Studies of Immunogenity, Protectivity, and Safety of the Combined Vector Vaccine for Prevention of the Middle East Respiratory Syndrome.

The Middle East Respiratory Syndrome (MERS) is an acute inflammatory disease of the respiratory system caused by the MERS-CoV coronavirus. The mortality rate for MERS is about 34.5%. Due to its high mortality rate, the lack of therapeutic and prophylactic agents, and the continuing threat of the spread of MERS beyond its current confines, developing a vaccine is a pressing task, because vaccination would help limit the spread of MERS and reduce its death toll. We have developed a combined vector vaccine for the prevention of MERS based on recombinant human adenovirus serotypes 26 and 5. Studies of its immunogenicity have shown that vaccination of animals (mice and primates) induces a robust humoral immune response that lasts for at least six months. Studies of the cellular immune response in mice after vaccination showed the emergence of a specific CD4+ and CD8+ T cell response. A study of the vaccine protectivity conducted in a model of transgenic mice carrying the human DPP4 receptor gene showed that our vaccination protected 100% of the animals from the lethal infection caused by the MERS-CoV virus (MERS-CoV EMC/2012, 100LD50 per mouse). Studies of the safety and tolerability of the developed vaccine in rodents, rabbits, and primates showed a good safety profile and tolerance in animals; they revealed no contraindications for clinical testing.

Imaging differences between coronavirus disease 2019, severe acute respiratory syndrome, and Middle East respiratory syndrome.

Since the outbreak of Coronavirus Disease-19 (COVID-19) infection in December 2019 in Wuhan, the capital Hubei province, central of China, more than 4 million people have contracted the virus worldwide. Despite the imposed precautions, coronavirus disease-19 is rapidly spreading with human-to-human transmission resulting in more than 290,000 death as of May 13, 2020 according to World Health Organization (WHO). The aim of this study was to revise the characteristic imaging features of Sever Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS) during their outbreak, and to compare them with that of COVID-19, to familiarize radiologists with the imaging spectrum of corona-virus syndromes. This study will help in more understanding and characterisation of COVID-19 to support the global efforts in combating its worldwide outbreak.

Middle East Respiratory Syndrome (MERS) and novel coronavirus disease-2019 (COVID-19): From causes to preventions in Saudi Arabia.

Saudi Arabia is one of the countries that has been affected by COVID-19. At the beginning of March 2020, it revealed a steadily rising number of laboratory-confirmed cases. By 20th May 2020, 59,854 infected cases had been confirmed, with 329 deaths. To prevent a further outbreak of COVID-19, this article discusses the current understanding of COVID-19 and compares it with the outbreak of Middle East Respiratory Syndrome (MERS) in 2012 in Saudi Arabia. It also discusses the causes, transmission, symptoms, diagnosis, treatments and prevention measures to identify an applicable measure to control COVID-19.

Efficacy of Corticosteroids in Patients with SARS, MERS and COVID-19: A Systematic Review and Meta-Analysis.

(1) Background: The use of corticosteroids in critical coronavirus infections, including severe acute respiratory syndrome (SARS), Middle East Respiratory Syndrome (MERS), or Coronavirus disease 2019 (COVID-19), has been controversial. However, a meta-analysis on the efficacy of steroids in treating these coronavirus infections is lacking. (2) Purpose: We assessed a methodological criticism on the quality of previous published meta-analyses and the risk of misleading conclusions with important therapeutic consequences. We also examined the evidence of the efficacy of corticosteroids in reducing mortality in SARS, MERS and COVID-19. (3) Methods: PubMed, MEDLINE, Embase, and Web of Science were used to identify studies published until 25 April 2020, that reported associations between steroid use and mortality in treating SARS/MERS/COVID-19. Two investigators screened and extracted data independently. Searches were restricted to studies on humans, and articles that did not report the exact number of patients in each group or data on mortality were excluded. We calculated odds ratios (ORs) or hazard ratios (HRs) under the fixed- and random-effect model. (4) Results: Eight articles (4051 patients) were eligible for inclusion. Among these selected studies, 3416 patients were diagnosed with SARS, 360 patients with MERS, and 275 with COVID-19; 60.3% patients were administered steroids. The meta-analyses including all studies showed no differences overall in terms of mortality (OR 1.152, 95% CI 0.631-2.101 in the random effects model, p = 0.645). However, this conclusion might be biased, because, in some studies, the patients in the steroid group had more severe symptoms than those in the control group. In contrast, when the meta-analysis was performed restricting only to studies that used appropriate adjustment (e.g., time, disease severity), there was a significant difference between the two groups (HR 0.378, 95% CI 0.221-0.646 in the random effects model, p < 0.0001). Although there was no difference in mortality when steroids were used in severe cases, there was a difference among the group with more underlying diseases (OR 3.133, 95% CI 1.670-5.877, p < 0.001). (5) Conclusions: To our knowledge, this study is the first comprehensive systematic review and meta-analysis providing the most accurate evidence on the effect of steroids in coronavirus infections. If not contraindicated, and in the absence of side effects, the use of steroids should be considered in coronavirus infection including COVID-19.

Does the novel coronavirus 2019 like heart more than the other family members of coronaviruses?

The disaster due to the novel coronavirus disease 2019 (COVID-19) around the world has made investigators enthusiastic about working on different aspects of COVID-19. However, although the pandemic of COVID-19 has not yet ended, it seems that COVID-19 compared to the other coronavirus infections (the Middle East Respiratory Syndrome [MERS] and Severe Acute Respiratory Syndrome [SARS]) is more likely to target the heart. Comparing the previous presentations of the coronavirus family and the recent cardiovascular manifestations of COVID-19 can also help in predicting possible future challenges and taking measures to tackle these issues.

Ultra-Rapid Real-Time RT-PCR Method for Detecting Middle East Respiratory Syndrome Coronavirus Using a Mobile PCR Device, PCR1100.

Middle East respiratory syndrome (MERS) coronavirus (MERS-CoV) is usually diagnosed through highly sensitive and specific genetic tests such as real-time reverse transcription polymerase chain reaction (RT-PCR). Currently, two real-time RT-PCR assays targeting the upE and ORF1a regions of the MERS-CoV genome are widely used, and these are the standard assays recommended by the World Health Organization (WHO). The MERS outbreaks to date suggest that rapid diagnosis and subsequent isolation of infected patients, particularly superspreaders, are critical for containment. However, conventional real-time RT-PCR assays require large laboratory instruments, and amplification takes approximately 2 h. These disadvantages limit rapid diagnosis. Here, an ultra-rapid real-time RT-PCR test was established comprising a multiplex assay for upE and ORF1a running on a mobile PCR1100 device. As few as five copies of the MERS-CoV RNA can be detected within 20 min using the standard WHO assays in the mobile PCR device, with the sensitivity and specificity being similar to those of a conventional real-time PCR instrument such as the LightCyler, thereby enabling timely intervention to control MERS-CoV infection.