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COVID-19: combining antiviral and anti-inflammatory treatments

Shakiba Darvishalipour
20 Apr 2020-Vol. 4, Iss: 7, pp 282-285
TL;DR: The potential for combination therapy with baracitinib is high, because of its low plasma protein binding and minimal interaction with CYP enzymes and drug transporters as discussed by the authors.
Abstract: The high affinity of baricitinib for the numb-associated kinase (NAK) family, its anti-inflammatory properties, with its advantageous pharmacokinetic properties, appear to make it a special case among the approved drugs. In addition, the potential for combination therapy with baracitinib is high, because of its low plasma protein binding and minimal interaction with CYP enzymes and drug transporters. Combinations of baricitinib with these direct-acting antivirals could reduce viral infectivity, viral replication, and the aberrant host inflammatory response. This work demonstrates that the use of an AI-driven knowledge graph can facilitate rapid drug development.
Citations
More filters
Journal Article•DOI•
Immune response in COVID-19: addressing a pharmacological challenge by targeting pathways triggered by SARS-CoV-2.

[...]

Michele Catanzaro1, Francesca Fagiani1, Francesca Fagiani2, Marco Racchi1, Emanuela Corsini3, Stefano Govoni1, Cristina Lanni1 •
University of Pavia1, Istituto Universitario Di Studi Superiori Di Pavia2, University of Milan3
29 May 2020-Signal Transduction and Targeted Therapy
TL;DR: Given the key role of the immune system in COVID-19, a deeper understanding of the mechanism behind the immune dysregulation might give clues for the clinical management of the severe cases and for preventing the transition from mild to severe stages
Abstract: To date, no vaccines or effective drugs have been approved to prevent or treat COVID-19 and the current standard care relies on supportive treatments. Therefore, based on the fast and global spread of the virus, urgent investigations are warranted in order to develop preventive and therapeutic drugs. In this regard, treatments addressing the immunopathology of SARS-CoV-2 infection have become a major focus. Notably, while a rapid and well-coordinated immune response represents the first line of defense against viral infection, excessive inflammatory innate response and impaired adaptive host immune defense may lead to tissue damage both at the site of virus entry and at systemic level. Several studies highlight relevant changes occurring both in innate and adaptive immune system in COVID-19 patients. In particular, the massive cytokine and chemokine release, the so-called "cytokine storm", clearly reflects a widespread uncontrolled dysregulation of the host immune defense. Although the prospective of counteracting cytokine storm is compelling, a major limitation relies on the limited understanding of the immune signaling pathways triggered by SARS-CoV-2 infection. The identification of signaling pathways altered during viral infections may help to unravel the most relevant molecular cascades implicated in biological processes mediating viral infections and to unveil key molecular players that may be targeted. Thus, given the key role of the immune system in COVID-19, a deeper understanding of the mechanism behind the immune dysregulation might give us clues for the clinical management of the severe cases and for preventing the transition from mild to severe stages.

469 citations

Cites background from "COVID-19: combining antiviral and a..."

  • ...Based on this anti-inflammatory effect, they are likely to be effective against the consequences of the elevated levels of cytokines typically observed in patients with COVID-19.(80) Among them, baricitinib, a selective inhibitor of JAK 1 and 2, has been predicted by crystallographic studies to inhibit two members of the numb-associated kinase family, such as AP2-associated protein kinase 1 (AAK1) and cyclin G-associated kinase (GAK), thus hindering viral endocytosis into lung cells, at the concentration approved for the treatment of arthritis rheumatoid....

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  • ...Interestingly, Gou et al.37 recently reported that the disruption of gut microbiome features by host and environmental factors may predispose healthy individuals to abnormal inflammatory response observed in COVID-19....

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  • ...Moreover, 18 clinical trials (typing COVID-19 and tocilizumab on clinicaltrials.gov and clinicaltrialsregister.eu) will study the efficacy and safety of another IL-6 receptor antagonist, sarilumab, approved for the treatment of rheumatoid arthritis in patients with COVID-19....

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  • ...In addition, concerning a potential intervention on NF-κB signaling pathway, serine protease inhibitors of trypsin-like serine proteases (e.g. camostat mesylate, nafamostat mesylate, gabexate mesylate, ulinastatin), used for the treatment of pancreatitis, disseminated intravascular coagulation, and anticoagulant for hemodialysis,55,56 have been found to inhibit viral replication57,58 and to attenuate inflammatory processes in different pathological contexts, such as asthma, chronic allergic pulmonary inflammation, and inflammatory myocardial injury.59–62 For instance, nafamostat mesylate and gabexate mesylate have been demonstrated to attenuate allergen-induced airway inflammation and eosinophilia in mouse model of allergic asthma,61 thus reducing mast cell activation, eosinophils infiltrations in the lung, and Dermatophagoides pteronyssinus-driven IL-4 and TNFα production in bronchoalveolar lavage fluid.61 Furthermore, treatment with nafamostat mesylate downregulated the expression of IL-1β, TNFα, IL-6, eotaxin, inducible NO synthase (iNOS), CD86, and NF-κB activation, but enhanced the expression of IL-12 and IL-10 in Dermatophagoides pteronyssinus-driven IL-4 and TNFα production in bronchoalveolar lavage fluid.61 Moreover, gabexate mesylate has been found to inhibit LPS-induced TNFα production in human monocytes by blocking both NF-κB and mitogen-activated protein kinase activation.63 Thus, the pharmacological profile of serine protease inhibitors, as inhibitors of complement pathways and broad-spectrum anti-inflammatory agents, provide a strong rationale for their use in the management of COVID-19....

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  • ...After the isolation of SARS-CoV-2, the viral genome was sequenced, thus facilitating diagnostic testing, epidemiologic tracking, as well as investigations on potential preventive and therapeutic strategies in the management of COVID-19....

    [...]

Journal Article•DOI•
Association of inflammatory markers with the severity of COVID-19: A meta-analysis.

[...]

Furong Zeng1, Yuzhao Huang1, Ying Guo1, Mingzhu Yin1, Xiang Chen1, Liang Xiao1, Guangtong Deng1 •
Central South University1
01 Jul 2020-International Journal of Infectious Diseases
TL;DR: A meta-analysis highlights the association of inflammatory markers with the severity of COVID-19 and suggests measurement ofinflammatory markers might assist clinicians to monitor and evaluate the severity and prognosis of CO VID-19.

373 citations

Cites background from "COVID-19: combining antiviral and a..."

  • ...Inflammatory responses triggered by rapid viral replication of SARS-CoV-2 and cellular destruction can recruit macrophages and monocytes and induce the release of cytokines and chemokines (Tay et al., 2020)....

    [...]

Journal Article•DOI•
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2): a global pandemic and treatment strategies.

[...]

Atul Sharma1, Swapnil Tiwari2, Manas Kanti Deb2, Jean-Louis Marty3•
Monash University, Clayton campus1, Pandit Ravishankar Shukla University2, University of Perpignan3
10 Jun 2020-International Journal of Antimicrobial Agents
TL;DR: The existing treatment is essentially supportive and role of antiviral agents is yet to be established as there is no vaccination or therapy available, and this review focuses on epidemiology, symptoms, transmission, pathogenesis, ongoing available treatments and future perspectives of SARS-CoV-2.

371 citations

Cites background from "COVID-19: combining antiviral and a..."

  • ...baricitinib for AAK1 and JAK, ability to ameliorate allied chronic inflammation in 524 interferonopathies, pharmacokinetic properties make it a potential candidate to combine with 525 the direct-acting antivirals (lopinavir or ritonavir and remdesivir) to combat with the SARS526 CoV-2 pandemic [98]....

    [...]

Journal Article•DOI•
Cytokine Storm in COVID-19-Immunopathological Mechanisms, Clinical Considerations, and Therapeutic Approaches: The REPROGRAM Consortium Position Paper.

[...]

Sonu Bhaskar1, Sonu Bhaskar2, Akansha Sinha2, Maciej Banach, Shikha Mittoo3, Robert Weissert4, Joseph S. Kass5, Santhosh Rajagopal6, Anupama R. Pai7, Shelby Kutty8 •
Liverpool Hospital1, University of New South Wales2, University of Toronto3, University of Regensburg4, Baylor College of Medicine5, World Health Organization6, National Institute of Mental Health and Neurosciences7, Johns Hopkins University8
10 Jul 2020-Frontiers in Immunology
TL;DR: An overview of the cytokine storm and its implications in COVID-19 settings is presented and potential pathways or biomarkers that could be targeted for therapy are identified.
Abstract: Cytokine storm is an acute hyperinflammatory response that may be responsible for critical illness in many conditions including viral infections, cancer, sepsis, and multi-organ failure The phenomenon has been implicated in critically ill patients infected with SARS-CoV-2, the novel coronavirus implicated in COVID-19 Critically ill COVID-19 patients experiencing cytokine storm are believed to have a worse prognosis and increased fatality rate In SARS-CoV-2 infected patients, cytokine storm appears important to the pathogenesis of several severe manifestations of COVID-19: acute respiratory distress syndrome, thromboembolic diseases such as acute ischemic strokes caused by large vessel occlusion and myocardial infarction, encephalitis, acute kidney injury, and vasculitis (Kawasaki-like syndrome in children and renal vasculitis in adult) Understanding the pathogenesis of cytokine storm will help unravel not only risk factors for the condition but also therapeutic strategies to modulate the immune response and deliver improved outcomes in COVID-19 patients at high risk for severe disease In this article, we present an overview of the cytokine storm and its implications in COVID-19 settings and identify potential pathways or biomarkers that could be targeted for therapy Leveraging expert opinion, emerging evidence, and a case-based approach, this position paper provides critical insights on cytokine storm from both a prognostic and therapeutic standpoint

345 citations

Journal Article•DOI•
A review on the cleavage priming of the spike protein on coronavirus by angiotensin-converting enzyme-2 and furin.

[...]

Anwarul Hasan1, Bilal Ahamad Paray2, Arif Hussain3, Fikry Ali Qadir4, Farnoosh Attar5, Falah Mohammad Aziz4, Majid Sharifi6, Hossein Derakhshankhah7, Behnam Rasti6, Masoumeh Mehrabi6, Koorosh Shahpasand8, Ali Akbar Saboury9, Mojtaba Falahati6 •
Qatar University1, King Saud University2, Manipal University3, Salahaddin University4, United States Department of Agriculture5, Islamic Azad University6, Kermanshah University of Medical Sciences7, Royan Institute8, University of Tehran9
22 Apr 2020-Journal of Biomolecular Structure & Dynamics
TL;DR: This review surveyed the role of furin cleavage site (FCS) on the life cycle of the CoV and discussed that the small molecular inhibitors can limit the interaction of ACE-2 and furin with SP and can be used as potential therapeutic platforms to combat the spreading CoV epidemic.
Abstract: The widespread antigenic changes lead to the emergence of a new type of coronavirus (CoV) called as severe acute respiratory syndrome (SARS)-CoV-2 that is immunologically different from the previous circulating species. Angiotensin-converting enzyme-2 (ACE-2) is one of the most important receptors on the cell membrane of the host cells (HCs) which its interaction with spike protein (SP) with a furin-cleavage site results in the SARS-CoV-2 invasion. Hence, in this review, we presented an overview on the interaction of ACE-2 and furin with SP. As several kinds of CoVs, from various genera, have at their S1/S2 binding site a preserved site, we further surveyed the role of furin cleavage site (FCS) on the life cycle of the CoV. Furthermore, we discussed that the small molecular inhibitors can limit the interaction of ACE-2 and furin with SP and can be used as potential therapeutic platforms to combat the spreading CoV epidemic. Finally, some ongoing challenges and future prospects for the development of potential drugs to promote targeting specific activities of the CoV were reviewed. In conclusion, this review may pave the way for providing useful information about different compounds involved in improving the effectiveness of CoV vaccine or drugs with minimum toxicity against human health.Communicated by Ramaswamy H. Sarma.

242 citations

Cites background from "COVID-19: combining antiviral and a..."

  • ...; Changes in these regions affect the antibodies produced against the former strains, and therefore have no role in the immunity against this disease (Stebbing et al., 2020)....

    [...]

References
More filters
Journal Article•DOI•
Immune response in COVID-19: addressing a pharmacological challenge by targeting pathways triggered by SARS-CoV-2.

[...]

Michele Catanzaro1, Francesca Fagiani1, Francesca Fagiani2, Marco Racchi1, Emanuela Corsini3, Stefano Govoni1, Cristina Lanni1 •
University of Pavia1, Istituto Universitario Di Studi Superiori Di Pavia2, University of Milan3
29 May 2020-Signal Transduction and Targeted Therapy
TL;DR: Given the key role of the immune system in COVID-19, a deeper understanding of the mechanism behind the immune dysregulation might give clues for the clinical management of the severe cases and for preventing the transition from mild to severe stages
Abstract: To date, no vaccines or effective drugs have been approved to prevent or treat COVID-19 and the current standard care relies on supportive treatments. Therefore, based on the fast and global spread of the virus, urgent investigations are warranted in order to develop preventive and therapeutic drugs. In this regard, treatments addressing the immunopathology of SARS-CoV-2 infection have become a major focus. Notably, while a rapid and well-coordinated immune response represents the first line of defense against viral infection, excessive inflammatory innate response and impaired adaptive host immune defense may lead to tissue damage both at the site of virus entry and at systemic level. Several studies highlight relevant changes occurring both in innate and adaptive immune system in COVID-19 patients. In particular, the massive cytokine and chemokine release, the so-called "cytokine storm", clearly reflects a widespread uncontrolled dysregulation of the host immune defense. Although the prospective of counteracting cytokine storm is compelling, a major limitation relies on the limited understanding of the immune signaling pathways triggered by SARS-CoV-2 infection. The identification of signaling pathways altered during viral infections may help to unravel the most relevant molecular cascades implicated in biological processes mediating viral infections and to unveil key molecular players that may be targeted. Thus, given the key role of the immune system in COVID-19, a deeper understanding of the mechanism behind the immune dysregulation might give us clues for the clinical management of the severe cases and for preventing the transition from mild to severe stages.

469 citations

Journal Article•DOI•
Association of inflammatory markers with the severity of COVID-19: A meta-analysis.

[...]

Furong Zeng1, Yuzhao Huang1, Ying Guo1, Mingzhu Yin1, Xiang Chen1, Liang Xiao1, Guangtong Deng1 •
Central South University1
01 Jul 2020-International Journal of Infectious Diseases
TL;DR: A meta-analysis highlights the association of inflammatory markers with the severity of COVID-19 and suggests measurement ofinflammatory markers might assist clinicians to monitor and evaluate the severity and prognosis of CO VID-19.

373 citations

Journal Article•DOI•
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2): a global pandemic and treatment strategies.

[...]

Atul Sharma1, Swapnil Tiwari2, Manas Kanti Deb2, Jean-Louis Marty3•
Monash University, Clayton campus1, Pandit Ravishankar Shukla University2, University of Perpignan3
10 Jun 2020-International Journal of Antimicrobial Agents
TL;DR: The existing treatment is essentially supportive and role of antiviral agents is yet to be established as there is no vaccination or therapy available, and this review focuses on epidemiology, symptoms, transmission, pathogenesis, ongoing available treatments and future perspectives of SARS-CoV-2.

371 citations

Journal Article•DOI•
Cytokine Storm in COVID-19-Immunopathological Mechanisms, Clinical Considerations, and Therapeutic Approaches: The REPROGRAM Consortium Position Paper.

[...]

Sonu Bhaskar1, Sonu Bhaskar2, Akansha Sinha2, Maciej Banach, Shikha Mittoo3, Robert Weissert4, Joseph S. Kass5, Santhosh Rajagopal6, Anupama R. Pai7, Shelby Kutty8 •
Liverpool Hospital1, University of New South Wales2, University of Toronto3, University of Regensburg4, Baylor College of Medicine5, World Health Organization6, National Institute of Mental Health and Neurosciences7, Johns Hopkins University8
10 Jul 2020-Frontiers in Immunology
TL;DR: An overview of the cytokine storm and its implications in COVID-19 settings is presented and potential pathways or biomarkers that could be targeted for therapy are identified.
Abstract: Cytokine storm is an acute hyperinflammatory response that may be responsible for critical illness in many conditions including viral infections, cancer, sepsis, and multi-organ failure The phenomenon has been implicated in critically ill patients infected with SARS-CoV-2, the novel coronavirus implicated in COVID-19 Critically ill COVID-19 patients experiencing cytokine storm are believed to have a worse prognosis and increased fatality rate In SARS-CoV-2 infected patients, cytokine storm appears important to the pathogenesis of several severe manifestations of COVID-19: acute respiratory distress syndrome, thromboembolic diseases such as acute ischemic strokes caused by large vessel occlusion and myocardial infarction, encephalitis, acute kidney injury, and vasculitis (Kawasaki-like syndrome in children and renal vasculitis in adult) Understanding the pathogenesis of cytokine storm will help unravel not only risk factors for the condition but also therapeutic strategies to modulate the immune response and deliver improved outcomes in COVID-19 patients at high risk for severe disease In this article, we present an overview of the cytokine storm and its implications in COVID-19 settings and identify potential pathways or biomarkers that could be targeted for therapy Leveraging expert opinion, emerging evidence, and a case-based approach, this position paper provides critical insights on cytokine storm from both a prognostic and therapeutic standpoint

345 citations

Journal Article•DOI•
A review on the cleavage priming of the spike protein on coronavirus by angiotensin-converting enzyme-2 and furin.

[...]

Anwarul Hasan1, Bilal Ahamad Paray2, Arif Hussain3, Fikry Ali Qadir4, Farnoosh Attar5, Falah Mohammad Aziz4, Majid Sharifi6, Hossein Derakhshankhah7, Behnam Rasti6, Masoumeh Mehrabi6, Koorosh Shahpasand8, Ali Akbar Saboury9, Mojtaba Falahati6 •
Qatar University1, King Saud University2, Manipal University3, Salahaddin University4, United States Department of Agriculture5, Islamic Azad University6, Kermanshah University of Medical Sciences7, Royan Institute8, University of Tehran9
22 Apr 2020-Journal of Biomolecular Structure & Dynamics
TL;DR: This review surveyed the role of furin cleavage site (FCS) on the life cycle of the CoV and discussed that the small molecular inhibitors can limit the interaction of ACE-2 and furin with SP and can be used as potential therapeutic platforms to combat the spreading CoV epidemic.
Abstract: The widespread antigenic changes lead to the emergence of a new type of coronavirus (CoV) called as severe acute respiratory syndrome (SARS)-CoV-2 that is immunologically different from the previous circulating species. Angiotensin-converting enzyme-2 (ACE-2) is one of the most important receptors on the cell membrane of the host cells (HCs) which its interaction with spike protein (SP) with a furin-cleavage site results in the SARS-CoV-2 invasion. Hence, in this review, we presented an overview on the interaction of ACE-2 and furin with SP. As several kinds of CoVs, from various genera, have at their S1/S2 binding site a preserved site, we further surveyed the role of furin cleavage site (FCS) on the life cycle of the CoV. Furthermore, we discussed that the small molecular inhibitors can limit the interaction of ACE-2 and furin with SP and can be used as potential therapeutic platforms to combat the spreading CoV epidemic. Finally, some ongoing challenges and future prospects for the development of potential drugs to promote targeting specific activities of the CoV were reviewed. In conclusion, this review may pave the way for providing useful information about different compounds involved in improving the effectiveness of CoV vaccine or drugs with minimum toxicity against human health.Communicated by Ramaswamy H. Sarma.

242 citations

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