Targeting Human Proteins for Antiviral Drug Discovery and Repurposing Efforts: A Focus on Protein Kinases.

Despite the great technological and medical advances in fighting viral diseases, new therapies for most of them are still lacking, and existing antivirals suffer from major limitations regarding drug resistance and a limited spectrum of activity. In fact, most approved antivirals are directly acting antiviral (DAA) drugs, which interfere with viral proteins and confer great selectivity towards their viral targets but suffer from resistance and limited spectrum. Nowadays, host-targeted antivirals (HTAs) are on the rise, in the drug discovery and development pipelines, in academia and in the pharmaceutical industry. These drugs target host proteins involved in the virus life cycle and are considered promising alternatives to DAAs due to their broader spectrum and lower potential for resistance. Herein, we discuss an important class of HTAs that modulate signal transduction pathways by targeting host kinases. Kinases are considered key enzymes that control virus-host interactions. We also provide a synopsis of the antiviral drug discovery and development pipeline detailing antiviral kinase targets, drug types, therapeutic classes for repurposed drugs, and top developing organizations. Furthermore, we detail the drug design and repurposing considerations, as well as the limitations and challenges, for kinase-targeted antivirals, including the choice of the binding sites, physicochemical properties, and drug combinations.

Analyzing the Systems Biology Effects of COVID-19 mRNA Vaccines to Assess Their Safety and Putative Side Effects.

COVID-19 vaccines have been instrumental tools in reducing the impact of SARS-CoV-2 infections around the world by preventing 80% to 90% of hospitalizations and deaths from reinfection, in addition to preventing 40% to 65% of symptomatic illnesses. However, the simultaneous large-scale vaccination of the global population will indubitably unveil heterogeneity in immune responses as well as in the propensity to developing post-vaccine adverse events, especially in vulnerable individuals. Herein, we applied a systems biology workflow, integrating vaccine transcriptional signatures with chemogenomics, to study the pharmacological effects of mRNA vaccines. First, we derived transcriptional signatures and predicted their biological effects using pathway enrichment and network approaches. Second, we queried the Connectivity Map (CMap) to prioritize adverse events hypotheses. Finally, we accepted higher-confidence hypotheses that have been predicted by independent approaches. Our results reveal that the mRNA-based BNT162b2 vaccine affects immune response pathways related to interferon and cytokine signaling, which should lead to vaccine success, but may also result in some adverse events. Our results emphasize the effects of BNT162b2 on calcium homeostasis, which could be contributing to some frequently encountered adverse events related to mRNA vaccines. Notably, cardiac side effects were signaled in the CMap query results. In summary, our approach has identified mechanisms underlying both the expected protective effects of vaccination as well as possible post-vaccine adverse effects. Our study illustrates the power of systems biology approaches in improving our understanding of the comprehensive biological response to vaccination against COVID-19.

Shedding the Light on Post-Vaccine Myocarditis and Pericarditis in COVID-19 and Non-COVID-19 Vaccine Recipients.

Myocarditis and pericarditis have been linked recently to COVID-19 vaccines without exploring the underlying mechanisms, or compared to cardiac adverse events post-non-COVID-19 vaccines. We introduce an informatics approach to study post-vaccine adverse events on the systems biology level to aid the prioritization of effective preventive measures and mechanism-based pharmacotherapy by integrating the analysis of adverse event reports from the Vaccine Adverse Event Reporting System (VAERS) with systems biology methods. Our results indicated that post-vaccine myocarditis and pericarditis were associated most frequently with mRNA COVID-19 vaccines followed by live or live-attenuated non-COVID-19 vaccines such as smallpox and anthrax vaccines. The frequencies of cardiac adverse events were affected by vaccine, vaccine type, vaccine dose, sex, and age of the vaccinated individuals. Systems biology results suggested a central role of interferon-gamma (INF-gamma) in the biological processes leading to cardiac adverse events, by impacting MAPK and JAK-STAT signaling pathways. We suggest that increasing the time interval between vaccine doses minimizes the risks of developing inflammatory adverse reactions. We also propose glucocorticoids as preferred treatments based on system biology evidence. Our informatics workflow provides an invaluable tool to study post-vaccine adverse events on the systems biology level to suggest effective mechanism-based pharmacotherapy and/or suitable preventive measures.

An Updated Review on SARS-CoV-2 Main Proteinase (MPro): Protein Structure and Small-Molecule Inhibitors.

[Coronaviruses (CoVs) are enveloped positive-stranded RNA viruses with spike (S) protein projections that allow the virus to enter and infect host cells. The S protein is a key virulence factor determining viral pathogenesis, host tropism, and disease pathogenesis. There are currently diverse corona viruses that are known to cause disease in humans. The occurrence of Middle East respiratory syndrome coronavirus (MERS-CoV) and Severe Acute Respiratory Syndrome coronavirus (SARS-CoV), as fatal human CoV diseases, has induced significant interest in the medical field. The novel coronavirus disease (COVID-19) is an infectious disease caused by a novel strain of coronavirus (SAR-CoV-2). The SARS-CoV2 outbreak has been evolved in Wuhan, China, in December 2019, and identified as a pandemic in March 2020, resulting in 53.24 M cases and 1.20M deaths worldwide. SARS-CoV-2 main proteinase (MPro), a key protease of CoV-2, mediates viral replication and transcription. SARS-CoV-2 MPro has been emerged as an attractive target for SARS-CoV-2 drug design and development. Diverse scaffolds have been released targeting SARS-CoV-2 MPro. In this review, we culminate the latest published information about SARS-CoV-2 main proteinase (MPro) and reported inhibitors.

The Influence of Coronavirus Diseases 2019 (COVID-19) Pandemic and the Quarantine Practices on University Students' Beliefs About the Online Learning Experience in Jordan.

Coronavirus Disease 2019 (COVID-19) is a contagious disease that affects the respiratory system. In addition to the severe effects of the disease on health, the pandemic caused a negative impact on basic needs and services, employment, education, and economy worldwide. In Jordan, the whole country locked down, and quarantine was enforced by the military forces, which successfully controlled the spread of the disease. This research aims to study the influence of the COVID-19 pandemic and its associated quarantine on university students' beliefs about online learning practice in Jordan. An online descriptive survey involved questions that covered students' demographic information, student's basic and advanced knowledge about COVID-19, students' online learning experience during the quarantine, and finally students' views on the enforced quarantine practice in Jordan. Results showed that students have a good knowledge (>50%) about the COVID-19 basic information and a moderate knowledge (<50%) regarding COVID-19 advanced information. In general, students were pessimistic about the future of COVID-19 both locally and worldwide. Although some students acknowledged that they learned new skills in the fields of electronics, informatics, and computer software during the pandemic, most of them were unsatisfied about the quality and quantity of the given material, online exams, and the evaluation processes. Unfortunately, most of the students faced internet technical problems or challenges to electronic accessibility. The majority of the participants (>90%) supported the military-enforced quarantine implemented in the country despite the hard time the students had during the quarantine. We conclude that university students were able to protect themselves from COVID-19 through their good knowledge about the infectious disease and their commitment to follow the rules imposed by the Government of Jordan. Nevertheless, the challenges caused by the pandemic and its associated quarantine, combined with the sudden unprecedented online experience, negatively impacted students' thoughts and beliefs about the online learning experience during the quarantine. Further studies need to be performed in this context. We hope our results will help decision-makers better understand the students' attitudes and motivation toward online learning and how this will affect their future plans and decisions.

An Updated Review on Betacoronavirus Viral Entry Inhibitors: Learning from Past Discoveries to Advance COVID-19 Drug Discovery.

Even after one year of its first outbreak reported in China, the coronavirus disease 2019 (COVID-19) pandemic is still sweeping the World, causing serious infections and claiming more fatalities. COVID-19 is caused by the novel coronavirus SARS-CoV-2, which belongs to the genus Betacoronavirus (ß-CoVs), which is of greatest clinical importance since it contains many other viruses that cause respiratory disease in humans, including OC43, HKU1, SARS-CoV, and MERS. The spike (S) glycoprotein of ß-CoVs is a key virulence factor in determining disease pathogenesis and host tropism, and it also mediates virus binding to the host's receptors to allow viral entry into host cells, i.e., the first step in virus lifecycle. Viral entry inhibitors are considered promising putative drugs for COVID-19. Herein, we mined the biomedical literature for viral entry inhibitors of other coronaviruses, with special emphasis on ß-CoVs entry inhibitors. We also outlined the structural features of SARS-CoV-2 S protein and how it differs from other ß-CoVs to better understand the structural determinants of S protein binding to its human receptor (ACE2). This review highlighted several promising viral entry inhibitors as potential treatments for COVID-19.

Chemocentric Informatics Analysis: Dexamethasone Versus Combination Therapy for COVID-19.

COVID-19 is a biphasic infectious disease with no approved vaccine or pharmacotherapy. The first drug that has shown promise in reducing COVID-19 mortality in severely-ill patients is dexamethasone, a cheap, well-known anti-inflammatory glucocorticoid, approved for the treatment of inflammatory conditions including respiratory diseases such as asthma and tuberculosis. However, about 80% of COVID-19 patients requiring oxygenation, and about 67% of patients on ventilators, are not responsive to dexamethasone therapy mainly. Additionally, using higher doses of dexamethasone for prolonged periods of time can lead to severe side effects and some patients may develop corticosteroid resistance leading to treatment failure. In order to increase the therapeutic efficacy of dexamethasone in COVID-19 patients, while minimizing dexamethasone-related complications that could result from using higher doses of the drug, we applied a chemocentric informatics approach to identify combination therapies. Our results indicated that combining dexamethasone with fast long-acting beta-2 adrenergic agonists (LABAs), such as formoterol and salmeterol, can ease respiratory symptoms hastily, until dexamethasone's anti-inflammatory and immunosuppressant effects kick in. Our studies demonstrated that LABAs and dexamethasone (or other glucocorticoids) exert synergistic effects that will augment both anti-inflammatory and fibronectin-mediated anticoagulant effects. We also propose other alternatives to LABAs that are supported by sound systems biology evidence, such as nitric oxide. Other drugs such as sevoflurane and treprostinil interact with the SARS-CoV-2 interactome and deserve further exploration. Moreover, our chemocentric informatics approach provides systems biology evidence that combination therapies for COVID-19 will have higher chances of perturbing the SARS-CoV-2 human interactome, which may negatively impact COVID-19 disease pathways.

Sitagliptin: a potential drug for the treatment of COVID-19?

Recently, an outbreak of a fatal coronavirus, SARS-CoV-2, has emerged from China and is rapidly spreading worldwide. Possible interaction of SARS-CoV-2 with DPP4 peptidase may partly contribute to the viral pathogenesis. An integrative bioinformatics approach starting with mining the biomedical literature for high confidence DPP4-protein/gene associations followed by functional analysis using network analysis and pathway enrichment was adopted. The results indicate that the identified DPP4 networks are highly enriched in viral processes required for viral entry and infection, and as a result, we propose DPP4 as an important putative target for the treatment of COVID-19. Additionally, our protein-chemical interaction networks identified important interactions between DPP4 and sitagliptin. We conclude that sitagliptin may be beneficial for the treatment of COVID-19 disease, either as monotherapy or in combination with other therapies, especially for diabetic patients and patients with pre-existing cardiovascular conditions who are already at higher risk of COVID-19 mortality.

A Systems Biology Workflow for Drug and Vaccine Repurposing: Identifying Small-Molecule BCG Mimics to Reduce or Prevent COVID-19 Mortality.

PURPOSE: Coronavirus disease 2019 (COVID-19) is expected to continue to cause worldwide fatalities until the World population develops 'herd immunity', or until a vaccine is developed and used as a prevention. Meanwhile, there is an urgent need to identify alternative means of antiviral defense. Bacillus Calmette-Guérin (BCG) vaccine that has been recognized for its off-target beneficial effects on the immune system can be exploited to boast immunity and protect from emerging novel viruses. METHODS: We developed and employed a systems biology workflow capable of identifying small-molecule antiviral drugs and vaccines that can boast immunity and affect a wide variety of viral disease pathways to protect from the fatal consequences of emerging viruses. RESULTS: Our analysis demonstrates that BCG vaccine affects the production and maturation of naïve T cells resulting in enhanced, long-lasting trained innate immune responses that can provide protection against novel viruses. We have identified small-molecule BCG mimics, including antiviral drugs such as raltegravir and lopinavir as high confidence hits. Strikingly, our top hits emetine and lopinavir were independently validated by recent experimental findings that these compounds inhibit the growth of SARS-CoV-2 in vitro. CONCLUSIONS: Our results provide systems biology support for using BCG and small-molecule BCG mimics as putative vaccine and drug candidates against emergent viruses including SARS-CoV-2.