Ibuprofen in the Management of Viral Infections: The Lesson of COVID-19 for Its Use in a Clinical Setting.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used for the management of fever, pain, and inflammation. However, they have always been considered to have a double-faced role, according to their capacity to manage inflammation but also their possible reduction of immune system response and diagnosis delay. This last point could favor a dramatic increase of viral infection diffusion, possibly leading to a more severe outcome. The advent of severe acute respiratory syndrome coronavirus 2 excluded the use of NSAIDs, particularly ibuprofen, and then indicated this drug as the better NSAID to manage infected outpatients and prevent complications. Several authors described the role of NSAIDs and ibuprofen in preventing cytokine storm and modulating the immune system. However, the development of both adverse drug reactions (i.e., gastrointestinal, renal, hepatic, and cardiovascular) and drug interaction recalled the necessity of prescribing the better NSAID for each patient. In this narrative review, we describe the role of NSAIDs, particularly of ibuprofen, in the management of viral symptoms, suggesting that the NSAID may be chosen considering the characteristics of the patient, the comorbidity, and the polytherapy.

The Matrix-M™ adjuvant: A critical component of vaccines for the 21st century.

Matrix-M™ adjuvant is a key component of several novel vaccine candidates. The Matrix-M adjuvant consists of two distinct fractions of saponins purified from the Quillaja saponaria Molina tree, combined with cholesterol and phospholipids to form 40-nm open cage-like nanoparticles, achieving potent adjuvanticity with a favorable safety profile. Matrix-M induces early activation of innate immune cells at the injection site and in the draining lymph nodes. This translates into improved magnitude and quality of the antibody response to the antigen, broadened epitope recognition, and the induction of a Th1-dominant immune response. Matrix-M-adjuvanted vaccines have a favorable safety profile and are well tolerated in clinical trials. In this review, we discuss the latest findings on the mechanisms of action, efficacy, and safety of Matrix-M adjuvant and other saponin-based adjuvants, with a focus on the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) subunit vaccine candidate NVX-CoV2373 developed to prevent coronavirus disease 2019 (COVID-19).

Favipiravir in the Spotlight: In Search of Treatment Against COVID-19

Background: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), sometimes referred to as the novel coronavirus (2019-nCoV), is currently a worldwide threat to public health. According to the Johns Hopkins University monitor (available at, coronavirus.jhu.edu/map), there have been more than 10 million reported cases of coronavirus 2019 disease (COVID-19) and 500,000 deaths as of June 29, 2020, deeming urgent the identification of a drug candidate and treatment regimen. Objective(s): This work aims to compile the current knowledge available on this drug, including its background, approved uses, some synthetic methods, the primary pharmacological aspects, the results against COVID-19 reported so far, and ongoing clinical trials against COVID-19. Method(s): We reviewed relevant press releases, scientific articles, and official documents to compile information about Favipiravir. Result(s): We highlight, in a clear and concise form, not only the published and ongoing clinical trials on the use of Favipiravir against COVID-19 but also compile some relevant synthetic and pharmacological information available about this drug. Conclusion(s): The Antiviral Favipiravir has shown interesting preliminary results, but it seems too early to recommend a treatment protocol for COVID-19 based on this drug. Robust clinical trials that will provide less biased data on its efficacy and safety are being pushed forward by FUJIFILM Corporation and by research groups around the globe.Copyright © 2021 Bentham Science Publishers.

Bromhexine: Into the spotlight

Bromhexine is a synthetic molecule derived from the natural product vasicinone isolated from Adhatoda vasica, an important ayurvedic medicinal plant. Bromhexine was validated as an active ingredient for pharmaceutical use at Boehringer Ingelheim and was introduced in 1963. Bromhexine is widely prescribed as OTC mucoactive drug to treat a broad range of respiratory diseases. The mechanism of action of bromhexine is primarily associated with its secretomotoric effect through expectorating the mucus out of the lungs with the modification in the physiochemical features of mucus. Bromhexine has been recently in the spotlight for its possible application as a repurposing drug candidate for the management of COVID-19 patients. In this chapter, we have provided a perspective for the application of bromhexine in COVID-19 patients based on the safety assessment, mechanistic findings, and reports from many clinical trials around the world. The chapter also tried to shed light on the therapeutic aspects of bromhexine in different disease conditions. © 2023 Elsevier Inc. All rights reserved.

Antiviral Potential of the Genus Panax: An updated review on their effects and underlying mechanism of action.

Viral infections are known as one of the major factors causing death. Ginseng is a medicinal plant that demonstrated a wide range of antiviral potential, and saponins are the major bioactive ingredients in the genus Panax with vast therapeutic potential. Studies focusing on the antiviral activity of the genus Panax plant-derived agents (extracts and saponins) and their mechanisms were identified and summarized, including contributions mainly from January 2016 until January 2022. P. ginseng, P. notoginseng, and P. quinquefolius were included in the review as valuable medicinal herbs against infections with 14 types of viruses. Reports from 9 extracts and 12 bioactive saponins were included, with 6 types of protopanaxadiol (PPD) ginsenosides and 6 types of protopanaxatriol (PPT) ginsenosides. The mechanisms mainly involved the inhibition of viral attachment and replication, the modulation of immune response by regulating signaling pathways, including the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway, cystathionine γ-lyase (CSE)/hydrogen sulfide (H2S) pathway, phosphoinositide-dependent kinase-1 (PDK1)/ protein kinase B (Akt) signaling pathway, c-Jun N-terminal kinase (JNK)/activator protein-1 (AP-1) pathway, and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway. This review includes detailed information about the mentioned antiviral effects of the genus Panax extracts and saponins in vitro and in vivo, and in human clinical trials, which provides a scientific basis for ginseng as an adjunctive therapeutic drug or nutraceutical.

Molecular Characterization of AZD7442 (Tixagevimab-Cilgavimab) Neutralization of SARS-CoV-2 Omicron Subvariants.

Therapeutic anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) monoclonal antibodies (MAbs) provide immunosuppressed and vulnerable populations with prophylactic and treatment interventions against coronavirus disease 2019 (COVID-19). AZD7442 (tixagevimab-cilgavimab) is a combination of extended-half-life neutralizing MAbs that bind to distinct epitopes on the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. The Omicron variant of concern carries mutations at >35 positions in the spike protein and has undergone further genetic diversification since its emergence in November 2021. Here, we characterize the in vitro neutralization activity of AZD7442 toward major viral subvariants circulating worldwide during the first 9 months of the Omicron wave. BA.2 and its derived subvariants showed the highest susceptibility to AZD7442, while BA.1 and BA.1.1 showed a lower susceptibility. BA.4/BA.5 had a susceptibility level intermediate between BA.1 and BA.2. Mutagenesis of parental Omicron subvariant spike proteins was performed to establish a molecular model to describe the underlying determinants of neutralization by AZD7442 and its component MAbs. The concurrent mutation of residues at positions 446 and 493, located in the tixagevimab and cilgavimab binding sites, was sufficient to enhance in vitro susceptibility of BA.1 to AZD7442 and its component MAbs to levels similar to the Wuhan-Hu-1+D614G virus. AZD7442 maintained neutralization activity against all Omicron subvariants tested up to and including BA.5. The evolving nature of the SARS-CoV-2 pandemic warrants continuing real-time molecular surveillance and assessment of in vitro activity of MAbs used in prophylaxis against and the treatment of COVID-19. IMPORTANCE MAbs are key therapeutic options for COVID-19 prophylaxis and treatment in immunosuppressed and vulnerable populations. Due to the emergence of SARS-CoV-2 variants, including Omicron, it is vital to ensure that neutralization is maintained for MAb-based interventions. We studied the in vitro neutralization of AZD7442 (tixagevimab-cilgavimab), a cocktail of two long-acting MAbs targeting the SARS-CoV-2 spike protein, toward Omicron subvariants circulating from November 2021 to July 2022. AZD7442 neutralized major Omicron subvariants up to and including BA.5. The mechanism of action responsible for the lower in vitro susceptibility of BA.1 to AZD7442 was investigated using in vitro mutagenesis and molecular modeling. A combination of mutations at two spike protein positions, namely, 446 and 493, was sufficient to enhance BA.1 susceptibility to AZD7442 to levels similar to the Wuhan-Hu-1+D614G ancestral virus. The evolving nature of the SARS-CoV-2 pandemic warrants continuing real-time global molecular surveillance and mechanistic studies of therapeutic MAbs for COVID-19.

Prospective mode of action of Ivermectin: SARS-CoV-2.

The well-known anti-helminthic drug ivermectin (IVM) has been established as an example of drug repurposing for the management of SARS-CoV-2 infection. Various study has been done to understand the inhibitory mechanism of IVM against SARS-CoV-2 targets. Broadly, IVM has been categorized as a host-directed agent and the proposed mechanism involves inhibition of the IMPα/ß1-mediated nuclear import of viral proteins. In addition, in vitro/in vivo and molecular docking/dynamic simulation studies suggested multitargets mechanism of IVM against SARS-CoV-2. Present manuscript attempts to provide an overview of the detailed mechanism of action based on experimental and computational studies. The knowledge of binding interaction of IVM and SARS-CoV-2 targets will give the direction to developed new and potential anti-COVID agents.

Potential Benefit of Vitamin D Supplementation in COVID-19.

Vitamin D is an important nutrient in the body that plays a vital role in immune system function. Several epidemiologic studies have shown that low vitamin D levels are found in a large percentage of COVID-19 patients with acute respiratory failure and that vitamin D levels may predict mortality in COVID-19 infection. Based on these findings, vitamin D supplementation may be an effective approach to preventing and/or treating COVID-19. Potential underlying mechanisms and clinical trial data evaluating the impact of supplementation in humans are described below.

The effects of lipoic acid on respiratory diseases

Respiratory diseases, including lung cancer, pulmonary fibrosis, asthma, and the recently emerging fatal coronavirus disease-19 (COVID-19), are the leading causes of illness and death worldwide. The increasing incidence and mortality rates have attracted much attention to the prevention and treatment of these conditions. Lipoic acid (LA), a naturally occurring organosulfur compound, is not only essential for mitochondrial aerobic metabolism but also shows therapeutic potential via certain pharmacological effects (e.g., antioxidative and anti-inflammatory effects). In recent years, accumulating evidence (animal experiments and in vitro studies) has suggested a role of LA in ameliorating many respiratory diseases (e.g., lung cancer, fibrosis, asthma, acute lung injury and smoking-induced lung injury). Therefore, this review will provide an overview of the present investigational evidence on the therapeutic effect of LA against respiratory diseases in vitro and in vivo. We also summarize the corresponding mechanisms of action to inspire further basic studies and clinical trials to confirm the health benefits of LA in the context of respiratory diseases.

Pathophysiology of SARS-CoV-2 Infection of Nasal Respiratory and Olfactory Epithelia and Its Clinical Impact.

PURPOSE OF REVIEW: While the predominant cause for morbidity and mortality with SARS-CoV-2 infection is the lower respiratory tract manifestations of the disease, the effects of SARS-CoV-2 infection on the sinonasal tract have also come to the forefront especially with the increased recognition of olfactory symptom. This review presents a comprehensive summary of the mechanisms of action of the SARS-CoV-2 virus, sinonasal pathophysiology of COVID-19, and the correlation with the clinical and epidemiological impact on olfactory dysfunction. RECENT FINDINGS: ACE2 and TMPRSS2 receptors are key players in the mechanism of infection of SARS-CoV-2. They are present within both the nasal respiratory as well as olfactory epithelia. There are however differences in susceptibility between different groups of individuals, as well as between the different SARS-CoV-2 variants. The sinonasal cavity is an important route for SARS-CoV-2 infection. While the mechanism of infection of SARS-CoV-2 in nasal respiratory and olfactory epithelia is similar, there exist small but significant differences in the susceptibility of these epithelia and consequently clinical manifestations of the disease. Understanding the differences and nuances in sinonasal pathophysiology in COVID-19 would allow the clinician to predict and counsel patients suffering from COVID-19. Future research into molecular pathways and cytokine responses at different stages of infection and different variants of SARS-CoV-2 would evaluate the individual clinical phenotype, prognosis, and possibly response to vaccines and therapeutics.

Discussions of Chemical, Biological, and Economic Features of two FDA Authorized Antivirals Against COVID-19: Molnupiravir and Paxlovid

Molnupiravir from Merck and Paxlovid from Pfizer are both promising. Since December 2019, the COVID-19 pandemic due to infection of SARS-CoV-2 has posed a challenge to global healthcare systems. Although vaccines and potential treatments have been developed, there are still many unknown areas of this virus, and people are still searching for efficient ways to treat the disease. Recently, two oral antivirals for COVID-19, Molnupiravir from Merck and Paxlovid from Pfizer, were developed and given emergency use authorization (EUA) from the U.S. FDA to reduce hospitalizations and death from COVID-19. Though the mechanism of action of the two drugs is very different, both drugs have shown promising efficacy in treating COVID-19 infections. This paper will compare these two drugs in various aspects, including their chemical structures, mechanism of action, efficacy and safety, and drug economics. © 2022 ACM.

Mechanism of "Child prevention prescription" of Hunan province in prevention and treatment of COVID-19 based on network pharmacology and molecular docking

To analyze the mechanism of novel coronavirus prevention prescription in Hunan province by using network pharmacology method. Methods TCMSP, Batman-TCM and ETCM were used to retrieve drug composition and target information, and GeneCards, OMIM, DrugBank, TTD and PharmGkb were used to screen disease targets. The visualization network diagram of "drug-active component-target" was constructed by Cytoscape, the protein interaction network was drawn by STRING, the core targets of PPI network were analyzed by CytoNCA, GO function and KEGG pathway were analyzed, and the mechanism of action was predicted. Results A total of 418 active ingredients, 1 715 drug targets, 1 289 disease targets and 266 intersection targets were screened out. Quercetin, luteolin, kaempferol, baicalein, ursolic acid and naringin were identified as the key components, and 6 core targets were obtained: RELA, AKT1, STAT3, JUN, MAPK1 and MAPK3. The results of molecular docking showed that the binding potential and activity of the key active ingredients to the core target were good. Conclusions "Child prevention formula" has the characteristics of multi-target, multi-approach and multi-faceted prevention and treatment, which plays a role in prevention and treatment of COVID-19 among children. Copyright © 2022 Publication Centre of Anhui Medical University. All rights reserved.

Present therapeutic and diagnostic approaches for SARS-CoV-2 infection

The novel Coronavirus (nCoV), severe acute respiratory syndrome-Coronavirus-2 (SARS-CoV-2), has shaken the whole world and posed significant challenges to the global healthcare system for more than a year. The scientific community across the globe is trying to combat this virus by developing a safe vaccine that can provide long-term immunity against the virus. The other means of overcoming its pathogenicity is to treat the infected people with available drugs and/or novel therapeutic strategies. The available drugs were previously designed to combat viral infections and come with tested safety. This appears to be the most practical approach as a quick response to the highly infectious pandemic with high morbidity and mortality. Although many repurposed drugs like favipiravir and hydroxychloroquine have been tried, they have been proven toxic and/or less efficacious. This has led the world to find urgent therapeutic interventions (traditional and novel), to help decrease the severity of COVID-19 infection and aim towards recovery. This chapter of the book will discuss the most up-to-date published data with respect to prevention and treatment of COVID-19 infection. Diagnosis also plays an important part in controlling the pandemic caused by the virus. A cheap, accurate and fast identification test for the virus is the need of the hour. This chapter will also throw light on the various diagnostic procedures available for the identification of SARS-CoV-2, till date, along with their advantages and disadvantages. © 2022 Elsevier Inc. All rights reserved.

Inorganic-based Surface Materials with Anti-SARS-CoV-2 Properties and Their Mechanisms of Action

The COVID-19 outbreak caused by SARS-CoV-2 has posed a serious threat to human health. The wide⁃ spread of the virus has increased the demand for anti-virus surface materials，especially in public places. This article reviews a series of inorganic surface materials with antiviral properties，including metals and its derivatives，graphene and its derivatives，and zeolites，and their antiviral mechanisms. The challenges and development prospects are summarized and prospected. © 2022 Higher Education Press. All rights reserved.

Potential common mechanism of four Chinese patent medicines recommended by diagnosis and treatment protocol for COVID-19 in medical observation period.

The global epidemic has been controlled to some extent, while sporadic outbreaks still occur in some places. It is essential to summarize the successful experience and promote the development of new drugs. This study aimed to explore the common mechanism of action of the four Chinese patent medicine (CPMs) recommended in the Medical Observation Period COVID-19 Diagnostic and Treatment Protocol and to accelerate the new drug development process. Firstly, the active ingredients and targets of the four CPMs were obtained by the Chinese medicine composition database (TCMSP, TCMID) and related literature, and the common action targets of the four TCMs were sorted out. Secondly, the targets of COVID-19 were obtained through the gene-disease database (GeneCards, NCBI). Then the Venn diagram was used to intersect the common drug targets with the disease targets. And GO and KEGG pathway functional enrichment analysis was performed on the intersected targets with the help of the R package. Finally, the results were further validated by molecular docking and molecular dynamics analysis. As a result, a total of 101 common active ingredients and 21 key active ingredients of four CPMs were obtained, including quercetin, luteolin, acacetin, kaempferol, baicalein, naringenin, artemisinin, aloe-emodin, which might be medicinal substances for the treatment of COVID-19. TNF, IL6, IL1B, CXCL8, CCL2, IL2, IL4, ICAM1, IFNG, and IL10 has been predicted as key targets. 397 GO biological functions and 166 KEGG signaling pathways were obtained. The former was mainly enriched in regulating apoptosis, inflammatory response, and T cell activation. The latter, with 92 entries related to COVID-19, was mainly enriched to signaling pathways such as Coronavirus disease-COVID-19, Cytokine-cytokine receptor interaction, IL-17 signaling pathway, and Toll-like receptor signaling pathway. Molecular docking results showed that 19/21 of key active ingredients exhibited strong binding activity to recognized COVID-19-related targets (3CL of SARS-CoV-2, ACE2, and S protein), even better than one of these four antiviral drugs. Among them, shinflavanone had better affinity to 3CL, ACE2, and S protein of SARS-CoV-2 than these four antiviral drugs. In summary, the four CPMs may play a role in the treatment of COVID-19 by binding flavonoids such as quercetin, luteolin, and acacetin to target proteins such as ACE2, 3CLpro, and S protein and acting on TNF, IL6, IL1B, CXCL8, and other targets to participate in broad-spectrum antiviral, immunomodulatory and inflammatory responses.

Discovery and mechanism of action of Thonzonium bromide from an FDA-approved drug library with potent and broad-spectrum inhibitory activity against main proteases of human coronaviruses.

Although the effective drugs or vaccines have been developed to prevent the spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), their efficacy may be limited for the viral evolution and immune escape. Thus, it is urgently needed to develop the novel broad-spectrum antiviral agents to control the coronavirus disease 2019 (COVID-19) global pandemic. The 3C-like protease (3CLpro) is a highly conserved cysteine proteinase that plays a pivotal role in processing the viral polyprotein to create non-structural proteins (nsps) for replication and transcription of SARS-CoV-2, making it an attractive antiviral target for developing broad-spectrum antiviral agents against SARS-CoV-2. In this study, we identified Thonzonium bromide as an inhibitor of SARS-CoV-2 3CLpro with an IC50 value of 2.04 ± 0.25 µM by fluorescence resonance energy transfer (FRET)-based enzymatic inhibition assay from the FDA-approved drug library. Next, we determined the inhibitory activity of Thonzonium bromide analogues against SARS-CoV-2 3CLpro and analyzed their structure-activity relationship (SAR). Interestingly, Thonzonium bromide showed better inhibitory activity than other analogues. Further fluorescence quenching assay, enzyme kinetics analysis, circular dichroism (CD) analysis and molecular docking studies showed that Thonzonium bromide inhibited SARS-CoV-2 3CLpro activity by firmly occupying the catalytic site and inducing conformational changes of the protease. In addition, Thonzonium bromide didn't exhibit inhibitory activity on human chymotrypsin C (CTRC) and Dipeptidyl peptidase IV (DPP-IV), indicating that it had a certain selectivity. Finally, we measured the inhibitory activities of Thonzonium bromide against 3CLpro of SARS-CoV, MERS-CoV and HCoV-229E and found that it had the broad-spectrum inhibitory activity against the proteases of human coronaviruses. These results provide the possible mechanism of action of Thonzonium bromide, highlighting its potential efficacy against multiple human coronaviruses.

Promising Marine Natural Products for Tackling Viral Outbreaks: A Focus on Possible Targets and Structure-Activity Relationship.

Recently, people worldwide have experienced several outbreaks caused by viruses that have attracted much interest globally, such as HIV, Zika, Ebola, and the one being faced, SARSCoV-2 viruses. Unfortunately, the availability of drugs giving satisfying outcomes in curing those diseases is limited. Therefore, it is necessary to dig deeper to provide compounds that can tackle the causative viruses. Meanwhile, the efforts to explore marine natural products have been gaining great interest as the products have consistently shown several promising biological activities, including antiviral activity. This review summarizes some products extracted from marine organisms, such as seaweeds, seagrasses, sponges, and marine bacteria, reported in recent years to have potential antiviral activities tested through several methods. The mechanisms by which those compounds exert their antiviral effects are also described here, with several main mechanisms closely associated with the ability of the products to block the entry of the viruses into the host cells, inhibiting replication or transcription of the viral genetic material, and disturbing the assembly of viral components. In addition, the structure-activity relationship of the compounds is also highlighted by focusing on six groups of marine compounds, namely sulfated polysaccharides, phlorotannins, terpenoids, lectins, alkaloids, and flavonoids. In conclusion, due to their uniqueness compared to substances extracted from terrestrial sources, marine organisms provide abundant products having promising activities as antiviral agents that can be explored to tackle virus-caused outbreaks.

The Mechanism-Based Inactivation of CYP3A4 by Ritonavir: What Mechanism?

Ritonavir is the most potent cytochrome P450 (CYP) 3A4 inhibitor in clinical use and is often applied as a booster for drugs with low oral bioavailability due to CYP3A4-mediated biotransformation, as in the treatment of HIV (e.g., lopinavir/ritonavir) and more recently COVID-19 (Paxlovid or nirmatrelvir/ritonavir). Despite its clinical importance, the exact mechanism of ritonavir-mediated CYP3A4 inactivation is still not fully understood. Nonetheless, ritonavir is clearly a potent mechanism-based inactivator, which irreversibly blocks CYP3A4. Here, we discuss four fundamentally different mechanisms proposed for this irreversible inactivation/inhibition, namely the (I) formation of a metabolic-intermediate complex (MIC), tightly coordinating to the heme group; (II) strong ligation of unmodified ritonavir to the heme iron; (III) heme destruction; and (IV) covalent attachment of a reactive ritonavir intermediate to the CYP3A4 apoprotein. Ritonavir further appears to inactivate CYP3A4 and CYP3A5 with similar potency, which is important since ritonavir is applied in patients of all ethnicities. Although it is currently not possible to conclude what the primary mechanism of action in vivo is, it is unlikely that any of the proposed mechanisms are fundamentally wrong. We, therefore, propose that ritonavir markedly inactivates CYP3A through a mixed set of mechanisms. This functional redundancy may well contribute to its overall inhibitory efficacy.

New type of RNA virus replication inhibitor based on decahydro-closo-decaborate anion containing amino acid ester pendant group.

In this work, a synthetic approach to prepare an example of new class of the derivatives of the closo-decaborate anion with amino acids detached from the boron cluster by pendant group has been proposed and implemented. Compound Na2[B10H9-O(CH2)4C(O)-His-OMe] was isolated and characterized. This compound has an inorganic hydrophobic core which is the 10-vertex boron cage and the -O(CH2)4C(O)-His-OMe organic substituent. It has been shown to possess strong antiviral activity in vitro against modern strains of A/H1N1 virus at 10 and 5 µg/mL. The compound has been found to be non-cytotoxic up to 160 µg/mL. At the same time, the compound has been found to be inactive against SARS-CoV-2, indicating specific activity against RNA virus replication. Molecular docking of the target derivative of the closo-decaborate anion with a model of the transmembrane region of the M2 protein has been performed and the mechanism of its antiviral action is discussed.