Baricitinib: A Review of Pharmacology,Safety, and Emerging Clinical Experience in COVID-19

A hyperinflammatory response to severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection, reminiscent of cytokine release syndrome, has been implicated in the pathophysiology of acute respiratory distress syndrome and organ damage in patients with coronavirus disease 2019 (COVID-19). Agents that inhibit components of the pro-inflammatory cascade have garnered interest as potential treatment options with hopes that dampening the proinflammatory process may improve clinical outcomes. Baricitinib is a reversible Janus-associated kinase (JAK)-inhibitor that interrupts the signaling of multiple cytokines implicated in COVID-19 immunopathology. It may also have antiviral effects by targeting host factors that viruses rely for cell entry and by suppressing type I interferon driven angiotensin-converting-enzyme-2 upregulation. However, baricitinib’s immunosuppressive effects may be detrimental during acute viral infections by delaying viral clearance and increasing vulnerability to secondary opportunistic infections. The lack of reliable biomarkers to monitor patients’ immune status as illness evolves complicates deployment of immunosuppressive drugs like baricitinib. Furthermore, baricitinib carries the risk of increased thromboembolic events, which is concerning given the proclivity towards a hypercoagulable state in patients with COVID-19. In this article, we review available data on baricitinib with an emphasis on immunosuppressive and antiviral pharmacology, pharmacokinetics, safety, and current progress in COVID-19 clinical trials.     

Virtual screening and molecular dynamics simulation analysis of Forsythoside A as a plant-derived inhibitor of SARS-CoV-2 3CLpro

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a more severe strain of coronavirus (CoV) that was first emerged in China in 2019. Available antiviral drugs could be repurposed and natural compounds with antiviral activity could be safer and cheaper source of medicine for SARS-CoV-2. 78 natural antiviral compounds database was identified from literature and virtual screening technique was applied to identify potential 3-chymotrypsin-like protease (3CLpro) inhibitors. Molecular docking studies were conducted to analyze the main protease (3CLpro) and inhibitors interactions with key residues of active site of target protein (PDB ID: 6LU7), active site constitute the part of active domain I and II of 3CLpro. 10 compounds with highest dock score were subjected to calculate ADMET parameters to figure out drug-likeness. Molecular dynamic (MD) simulation of the selected lead was performed by Amber simulation package to understand the conformational changes in docked complex. MD simulations analysis (RMSD, RMSF, Rg, BF, HBs, and SASA plots) of lead bounded with 3CLpro, hence revealed the important structural turns and twists during MD simulations from 0 to 100 ns. MM-PBSA/GBSA methods has also been applied for the estimation binding free energy (BFE) of the selected lead-complex. The present study has identified lead compound “Forsythoside A” an active extract of Forsythia suspense as SARS-CoV-2 3CLpro inhibitor that can block the viral replication and translation. Structural analysis of target protein and lead compound performed in this study could contribute to the development of potential drug against SARS-CoV-2 infection.     

Multifactorial Traits of SARS-CoV-2 Cell Entry Related to Diverse Host Proteases and Proteins

The most effective way to control newly emerging infectious disease, such as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, is to strengthen preventative or therapeutic public health strategies before the infection spreads worldwide. However, global health systems remain at the early stages in anticipating effective therapeutics or vaccines to combat the SARS-CoV-2 pandemic. While maintaining social distance is the most crucial metric to avoid spreading the virus, symptomatic therapy given to patients on the clinical manifestations helps save lives. The molecular properties of SARS-CoV-2 infection have been quickly elucidated, paving the way to therapeutics, vaccine development, and other medical interventions. Despite this progress, the detailed biomolecular mechanism of SARS-CoV-2 infection remains elusive. Given virus invasion of cells is a determining factor for virulence, understanding the viral entry process can be a mainstay in controlling newly emerged viruses. Since viral entry is mediated by selective cellular proteases or proteins associated with receptors, identification and functional analysis of these proteins could provide a way to disrupt virus propagation. This review comprehensively discusses cellular machinery necessary for SARS-CoV-2 infection. Understanding multifactorial traits of the virus entry will provide a substantial guide to facilitate antiviral drug development.     

Repurposing carrimycin as an antiviral agent against human coronaviruses,including the currently pandemic SARS-CoV-2

COVID-19 pandemic caused by SARS-CoV-2 infection severely threatens global health and economic development. No effective antiviral drug is currently available to treat COVID-19 and any other human coronavirus infections. We report herein that a macrolide antibiotic, carrimycin, potently inhibited the cytopathic effects (CPE) and reduced the levels of viral protein and RNA in multiple cell types infected by human coronavirus 229E, OC43, and SARS-CoV-2. Time-of-addition and pseudotype virus infection studies indicated that carrimycin inhibited one or multiple post-entry replication events of human coronavirus infection. In support of this notion, metabolic labelling studies showed that carrimycin significantly inhibited the synthesis of viral RNA. Our studies thus strongly suggest that carrimycin is an antiviral agent against a broad-spectrum of human coronaviruses and its therapeutic efficacy to COVID-19 is currently under clinical investigation.     

Progress towards improving antiviral therapy for hepatitis C with hepatitis C virus polymerase inhibitors. Part I: Nucleoside analogues

Background: With an increasing worldwide burden of liver failure and liver cancer from chronic hepatitis C virus (HCV) infection, discovery and development efforts for new antiviral medicines for HCV are expanding rapidly. Two HCV protease inhibitors (PIs), telaprevir (VX950) and boceprevir (SCH503034), are now furthest along in clinical development, with Phase II data suggesting a potential treatment advance with triple combination regimens comprising a protease inhibitor, pegylated interferon and ribavirin. However, the current data suggest that such regimens will fail to produce sustained virologic responses in ≥ 30 – 40% of patients, and tolerance of interferon/ribavirin treatment regimens is often problematic; hence, there is a need for continued development of new anti-HCV agents to further optimize treatment efficacy and safety. The HCV polymerase (HCV Pol) is an attractive target for antiviral therapy because the gene sequences encoding HCV Pol are relatively conserved across the six main HCV genotypes and the emergence of viral resistance is expected to be relatively slow for pharmaceutical agents, such as nucleoside analogues, that are targeted to the active (catalytic) site of HCV Pol. Methods: This review (Part I) of HCV Pol inhibitors focuses on the scientific rationale and recent development progress for nucleoside-type HCV Pol inhibitors; a subsequent review (Part II) will assess progress with non-nucleosidic HCV Pol inhibitors. Results/conclusions: Early clinical data for several nucleosides targeted to HCV Pol indicate marked antiviral effects and a likelihood of relatively slow HCV resistance, consistent with the profile of nucleosidic inhibitors of HIV and hepatitis B virus infection and supporting potentially important roles for nucleoside agents in optimizing combination therapies for HCV infection. Optimally effective future anti-HCV therapies are likely to be based on multi-class treatment regimens combining polymerase and PIs, together with pegylated interferon and ribavirin or pharmaceutical agents from other mechanistic classes.     

Nucleosides and emerging viruses: A new story

With several US Food and Drug Administration (FDA)-approved drugs and high barriers to resistance, nucleoside and nucleotide analogs remain the cornerstone of antiviral therapies for not only herpesviruses, but also HIV and hepatitis viruses (B and C); however, with the exception of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), for which vaccines have been developed at unprecedented speed, there are no vaccines or small antivirals yet available for (re)emerging viruses, which are primarily RNA viruses. Thus, herein, we present an overview of ribonucleoside analogs recently developed and acting as inhibitors of the viral RNA-dependent RNA polymerase (RdRp). They are new lead structures that will be exploited for the discovery of new antiviral nucleosides.     

Bupleurum kaoi inhibits Coxsackie B virus type 1 infection of CCFS-1 cells by induction of type I interferons expression.

Coxsackie B virus type 1 (CVB1) infection is known to cause high morbidity and mortality in children, however, there is no effective drug for treating this disease. The present study aimed to examine the antiviral activity of Bupleurum kaoi (BK), a popular herbal drug for treating viral and bacterial infections, against CVB1 infection and its mechanisms of action. Our data showed that BK neutralized the CVB1-induced cytopathic effect in human neonatal foreskin fibroblast cell line (CCFS-1/KMC), with IC50 and EC50 values around 12.38 microg/ml and 50.93 microg/ml, respectively. Its CC50 and SI values were 883.56 microg/ml and 17.34, respectively. These results suggest that BK possessed anti-CVB1 activity, and showed no effect on CCFS-1 cell viability and growth at concentration 250 microg/ml. The time-of-addition studies showed that BK (50, 100 and 200 microg/ml) added at various time of preinfection (-1 to -3 h), coinfection (0 h) and postinfection (1-3 h) could inhibit CVB1 infection. Interestingly, BK also showed an inhibition on viral replication through the induction of IFN-alpha/beta expression. In conclusion, BK possessed antiviral activity against CVB1 infection. It interfered the early stage of viral replication and viral replication after infection through the induction of type I interferon expression.     

The mechanism of poly I:C-induced antiviral activity in peritoneal macrophage

Macrophages play an important role in defense against virus infection by intrinsic resistance and by extrinsic resistance. Since interferon-induced enzymes which are 2'-5' oligoadenylate synthetase and P1/eIF-2 protein kinase have been shown to be involved in the inhibition of viral replication, I examined the mechanism by which poly I:C, an interferon inducer, exerts its antiviral effects in inflammatory macrophages infected with herpes simplex virus type 1 (HSV-1). The data presented here demonstrate that poly I:C-induced antiviral activity is partially due to the activation of 2'-5' oligoadenylate synthetase. The activation of 2'-5' oligoadenylate A synthetase by poly I:C is also at least partly mediated via the production of interferon-beta. Taken together, these data indicate that interferon-beta produced in response to poly I:C acts in an autocrine manner to activate the 2'-5' oligoadenylate synthetase and to induce resistance to HSV-1.     

Identification of neuraminidase inhibitors by structure-based screening: promising new leads for influenza

Human influenza commonly known as seasonal flu which is caused by a RNA virus has been emerging as a major viral infection over the years. Virus neuraminidase inhibitors and M2 protein inhibitors are the agents which have been used to treat this viral infection. Among these two, viral neuraminidases named oseltamivir and zanamivir are most widely used as antiviral agents to treat influenza. But the recent emergence of resistance strains in the treatment with both zanamivir and oseltamivir creates a big problem to treat this viral infection effectively. In this study, we have designed 68 new human influenza virus neuraminidase inhibitors and reported them as new potential antiviral agents against the complex structure of influenza virus neuraminidase and sialic acid using various in silico tools and molecular docking analysis taking zanamivir as prototype.     

TANK-binding kinase 1 as a novel therapeutic target for viral diseases

Introduction: TANK-binding kinase 1 (TBK1) is vital for the induction of antiviral innate immune responses. Both RNA and DNA viral infection induces TBK1 activation, triggers phosphorylation of interferon regulatory factor (IRF) 3 and subsequent expression of type I interferons (IFNs; IFN-α/β). Type I IFNs can induce the expression of numerous antiviral genes called interferon-stimulated genes (ISGs) to build a remarkable antiviral state and limit viral replication. Thus, optimal TBK1 activity is crucial for IRF3-induced type I IFNs expression and ISGs-mediated viral elimination.

Areas covered: This review provides an overview of the diverse roles of TBK1 in antiviral innate immune responses, the regulatory mechanisms of TBK1 activity and the implication in antiviral development.

Expert opinion: TBK1 is a key kinase against antiviral infection via inducing type I IFNs expression. Multiple types of post-translational modifications of TBK1 tightly regulate TBK1 activity and subsequent TBK1-dependent antiviral responses. The identified regulators of TBK1 unveil regulatory mechanisms of host antiviral innate immunity and immuno-escape mechanism of virus provide strategies to control viral diseases by modulating TBK1 activity.     

干扰素-τ的研究进展

摘要了解干扰素τ（interferon tau，IFN-τ）研究现状。综述了近五年来干扰素-τ研究进展。干扰素-τ具有Ⅰ型干扰素的共同特性：具有抗病毒、抗细胞增生、免疫调节等功能。但IFN-τ在生物学功能方面有自身特点，它仅在胚胎滋养层细胞中表达，无需病毒诱导；另外，高浓度IFN-τ表现出较其他Ⅰ型干扰素较小的细胞毒性。IFN-τ作为一种新的Ⅰ型干扰素，它具有抗黄体溶解、抗病毒、免疫调节等生物学功能，特别是对反转录病毒抑制的高度特异性以及对自身免疫性疾病的免疫调节活性，且低细胞毒性这一特点，它将成为新型的分子药物。     

Repurposing of cyclophilin A inhibitors as broad-spectrum antiviral agents

Cyclophilin A (CypA) is linked to diverse human diseases including viral infections. With the worldwide emergence of severe acute respiratory coronavirus 2 (SARS-CoV-2), drug repurposing has been highlighted as a strategy with the potential to speed up antiviral development. Because CypA acts as a proviral component in hepatitis C virus, coronavirus and HIV, its inhibitors have been suggested as potential treatments for these infections. Here, we review the structure of cyclosporin A and sanglifehrin A analogs as well as synthetic micromolecules inhibiting CypA; and we discuss their broad-spectrum antiviral efficacy in the context of the virus lifecycle.     

CK2 inhibitors increase the sensitivity of HSV-1 to interferon-β

Herpes simplex virus type 1 (HSV-1) requires the activities of cellular kinases for efficient replication. The host kinase, CK2, has been shown or is predicted to modify several HSV-1 proteins and has been proposed to affect one or more steps in the viral life cycle. Furthermore, potential cellular and viral substrates of CK2 are involved in antiviral pathways and viral counter-defenses, respectively, suggesting that CK2 regulates these processes. Consequently, we tested whether pharmacological inhibitors of CK2 impaired HSV-1 replication, either alone or in combination with the cellular antiviral factor, interferon-β (IFN-β). Our results indicate that the use of CK2 inhibitors results in a minor reduction in HSV-1 replication but enhanced the inhibitory effect of IFN-β on replication. This effect was dependent on the HSV-1 E3 ubiquitin ligase, infected cell protein 0 (ICP0), which impairs several host antiviral responses, including that produced by IFN-β. Inhibitors of CK2 did not, however, impede the ability of ICP0 to induce the degradation of two cellular targets: the promyelocytic leukemia protein (PML) and the DNA-dependent protein kinase catalytic subunit (DNA-PKcs). Notably, this effect was only apparent for HSV-1, as the CK2 inhibitors did not enhance the antiviral effect of IFN-β on either vesicular stomatitis virus or adenovirus type 5. Thus, our data suggest that the activity of CK2 is required for an early function during viral infection that assists the growth of HSV-1 in IFN-β-treated cells.     

HR121 targeting HR2 domain in S2 subunit of spike protein can serve as a broad-spectrum SARS-CoV-2 inhibitor via intranasal administration

The continuously emerging SARS-CoV-2 variants pose a great challenge to the efficacy of current drugs, this necessitates the development of broad-spectrum antiviral drugs. In the previous study, we designed a recombinant protein, heptad repeat (HR) 121, as a variant-proof vaccine. Here, we found it can act as a fusion inhibitor and demonstrated broadly neutralizing activities against SARS-CoV-2 and its main variants. Structure analysis suggested that HR121 targets the HR2 domain in SARS-CoV-2 spike (S) 2 subunit to block virus-cell fusion. Functional experiments demonstrated that HR121 can bind HR2 at serological-pH and endosomal-pH, highlighting its inhibition capacity when SARS-CoV-2 enters via either cellular membrane fusion or endosomal route. Importantly, HR121 can effectively inhibit SARS-CoV-2 and Omicron variant pseudoviruses entering the cells, as well as block authentic SARS-CoV-2 and Omicron BA.2 replications in human pulmonary alveolar epithelial cells. After intranasal administration to Syrian golden hamsters, it can protect hamsters from SARS-CoV-2 and Omicron BA.2 infection. Together, our results suggest that HR121 is a potent drug candidate with broadly neutralizing activities against SARS-CoV-2 and its variants.     

法匹拉韦治疗新冠肺炎临床研究进展

新型冠状病毒肺炎(COVID-19)疫情在全球大流行,临床上迫切需要特异性抗病毒治疗药物.对已批准上市或正在临床开发的药物开展重定位研究是针对突发疫情快速寻找潜在治疗药物最为快速和高效的策略.法匹拉韦是一种广谱抗RNA病毒药物,在日本和中国已批准上市用于治疗流感,其作为抗新型冠状病毒感染的潜在药物,全球多个国家正在开展...     

Xiao chai hu tang inhibits CVB1 virus infection of CCFS-1 cells through the induction of Type I interferon expression

Coxsackie B virus type 1 (CVB1) infection is known to cause high morbidity and mortality in children, however, there is no effective drug for treating this disease. The present study aimed to examine the antiviral activity of xiao chai hu tang (XCHT), a popular herbal drug for treating viral and bacterial infections, against CVB1 infection and its mechanisms of action. Our data showed that XCHT neutralized the CVB1-induced cytopathic effect in human neonatal foreskin fibroblast cell line (CCFS-1/KMC), with IC50 (virus-induced cytopathic effect by 50%) and EC50 (concentration of 50% effectiveness) values around 12.39 and 50.93 microg/ml, respectively. Its CC50 (concentration of 50% cellular cytotoxicity) and SI (selective index) values were 945.75 microg/ml and 18.92, respectively. These results suggest that XCHT possessed anti-CVB1 activity, and showed no effect on CCFS-1 cell viability and growth at concentration 250 microg/ml. The time-of-addition studies showed that XCHT (50, 100 and 200 microg/ml) added at various time of preinfection (-1 to -3 h), coinfection (0 h) and postinfection (1 approximately 3 h) could inhibit CVB1 infection. Interestingly, XCHT also showed an inhibition on viral replication through the induction of IFN-alpha/beta expression. In conclusion, XCHT possessed antiviral activity against CVB1 infection. It interfered the early stage of viral replication (prophylactic effect) and viral replication after infection (therapeutic effect) through the induction of Type I interferon expression.     

Ⅰ型干扰素抗病毒信号通路失调介导的病理效应研究新进展

Ⅰ型干扰素（type Ⅰ interferon,IFN-Ⅰ）具有广谱抗病毒免疫保护效应,已在临床上用于治疗多种病毒性疾病。IFN-Ⅰ与特异性受体结合后,触发一个极其复杂的信号通路网络,诱导产生大量抗病毒蛋白来发挥抗病毒和免疫调节作用。在急性病毒感染如高致病性H5N1禽流感病毒感染中,IFN-Ⅰ信号通路过度活化诱发的细胞因子风暴会促使病情进一步恶化。而在慢性病毒感染如慢性HCV感染中,IFN-Ⅰ在发挥治疗作用的同时还能引起一系列病理效应。因此,探索在病毒性疾病发生发展进程中适时激活或阻断IFN-Ⅰ信号通路的研究,将有助于指导临床合理高效地使用IFN-Ⅰ。     

Enterovirus A71 antivirals: Past,present, and future

Enterovirus A71 (EV-A71) is a significant human pathogen, especially in children. EV-A71 infection is one of the leading causes of hand, foot, and mouth diseases (HFMD), and can lead to neurological complications such as acute flaccid myelitis (AFM) in severe cases. Although three EV-A71 vaccines are available in China, they are not broadly protective and have reduced efficacy against emerging strains. There is currently no approved antiviral for EV-A71. Significant progress has been made in developing antivirals against EV-A71 by targeting both viral proteins and host factors. However, viral capsid inhibitors and protease inhibitors failed in clinical trials of human rhinovirus infection due to limited efficacy or side effects. This review discusses major discoveries in EV-A71 antiviral development, analyzes the advantages and limitations of each drug target, and highlights the knowledge gaps that need to be addressed to advance the field forward.     

Calming the cytokine storm of COVID-19 through inhibition of JAK2/STAT3 signaling

The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the unprecedented COVID-19 pandemic, which has infected over 178 million people worldwide. Even with new vaccines, global herd immunity will not be reached soon. New cases and viral variants are being reported at an alarming rate. Effective antiviral treatment is urgently needed. Patients with severe COVID-19 suffer from life-threatening respiratory failure due to acute respiratory distress syndrome in their lungs, a leading cause of COVID-19 mortality. This lung hyper-inflammation is induced by virus-caused massive tissue damage that is associated with uncontrolled cytokine release, known as a cytokine storm, through JAK/STAT signaling pathways. Here, we review the FDA-approved JAK inhibitors that are being clinically evaluated and repurposed for the treatment of patients with severe COVID-19 by calming SARS-CoV-2 infection.