FASEB Bioadv. 2020 Apr 11;2(5):296-303. doi: 10.1096/fba.2020-00015. eCollection 2020 May.
The role of growth factor receptors in viral infections: An opportunity for drug repurposing against emerging viral diseases such as COVID-19?
Hubert Hondermarck 1 2, Nathan W Bartlett 1 2, Victor Nurcombe 3 4
Growth factor receptors are known to be involved in the process of viral infection. Many viruses not only use growth factor receptors to physically attach to the cell surface and internalize, but also divert receptor tyrosine kinase signaling in order to replicate. Thus, repurposing drugs that have initially been developed to target growth factor receptors and their signaling in cancer may prove to be a fast track to effective therapies against emerging new viral infections, including the coronavirus disease 19 (COVID-19).
Antiviral Res. 2015 Aug;120:40-7. doi: 10.1016/j.antiviral.2015.05.003. Epub 2015 May 16.
Inhibitors of cellular kinases with broad-spectrum antiviral activity for hemorrhagic fever viruses
Emma L Mohr 1, Laura K McMullan 2, Michael K Lo 2, Jessica R Spengler 2, Éric Bergeron 2, César G Albariño 2, Punya Shrivastava-Ranjan 2, Cheng-Feng Chiang 2, Stuart T Nichol 2, Christina F Spiropoulou 3, Mike Flint 2
Host cell kinases are important for the replication of a number of hemorrhagic fever viruses. We tested a panel of kinase inhibitors for their ability to block the replication of multiple hemorrhagic fever viruses. OSU-03012 inhibited the replication of Lassa, Ebola, Marburg and Nipah viruses, whereas BIBX 1382 dihydrochloride inhibited Lassa, Ebola and Marburg viruses. BIBX 1382 blocked both Lassa and Ebola virus glycoprotein-dependent cell entry. These compounds may be used as tools to understand conserved virus-host interactions, and implicate host cell kinases that may be targets for broad spectrum therapeutic intervention.
Pharm Res. 2020; 37(9): 167.
Repurposing of Kinase Inhibitors for Treatment of COVID-19
Ellen Weisberg,corresponding author1,2 Alexander Parent,1,2 Priscilla L. Yang,3,4 Martin Sattler,1,2,5 Qingsong Liu,6 Qingwang Liu,6 Jinhua Wang,7 Chengcheng Meng,1 Sara J. Buhrlage,8 Nathanael Gray,7 and James D. Griffin1,2
The outbreak of COVID-19, the pandemic disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spurred an intense search for treatments by the scientific community. In the absence of a vaccine, the goal is to target the viral life cycle and alleviate the lung-damaging symptoms of infection, which can be life-threatening. There are numerous protein kinases associated with these processes that can be inhibited by FDA-approved drugs, the repurposing of which presents an alluring option as they have been thoroughly vetted for safety and are more readily available for treatment of patients and testing in clinical trials. Here, we characterize more than 30 approved kinase inhibitors in terms of their antiviral potential, due to their measured potency against key kinases required for viral entry, metabolism, or reproduction. We also highlight inhibitors with potential to reverse pulmonary insufficiency because of their anti-inflammatory activity, cytokine suppression, or antifibrotic activity. Certain agents are projected to be dual-purpose drugs in terms of antiviral activity and alleviation of disease symptoms, however drug combination is also an option for inhibitors with optimal pharmacokinetic properties that allow safe and efficacious co-administration with other drugs, such as antiviral agents, IL-6 blocking agents, or other kinase inhibitors.
COVID-19, Vascular Endothelial Growth Factor (VEGF) and Iodide
14 Pages Posted: 22 May 2020 Last revised: 4 Jun 2020
Mika Turkia. Independent. Date Written: June 3, 2020
Recently, attention around COVID-19 has shifted from respiratory symptoms to endothelial and other symptoms. Angiotensin-converting enzyme 2 (ACE2) is the entry receptor for SARS-CoV-2. SARS-CoV-2 is known to downregulate ACE2.
Vascular endothelial growth factors (VEGFs) are considered a key factor in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). VEGF concentrations were observed to be significantly higher in both ICU and non-ICU COVID-19 patients than in healthy controls. Although VEGFs promote angiogenesis, neurogenesis and neuroprotection, they also induce vascular leakiness and permeability.
ACE2 antagonizes VEGF-A to reduce vascular permeability during acute lung injury. Also in breast cancer cells, ACE2 downregulated the expression of VEGF-A. Since SARS-CoV-2 downregulates ACE2, it likely cancels the VEGF-A-antagonizing effect of ACE2, leading to upregulation of VEGF and thus increase of vascular permeability and aggravation of endothelial damage. VEGF might be upregulated also in normoxic conditions.
Iodide is a VEGF modulator, increasing lymphatic system related VEGF-C/D expression while simultaneously suppressing endothelial cell related VEGF-A/B expression. It may thus revert VEGF-A/B increase caused by SARS-CoV-2 downregulation of ACE2.
Protein kinase B (Akt) induces protective nitric oxide (NO) production in endothelial cells, including inhibition of thrombosis and platelet aggregation. In one study, excess iodide activated PI3K/Akt pathway.
In addition, iodide was demonstrated to accumulate in upper airway secretions and inhibit viral infections by participating in a nonspecific, broad spectrum mechanism applicable to multiple types of viruses. Also, in a mouse model, iodide was observed to protect against ischemia-reperfusion injury, which may be relevant for e.g. COVID-19 associated acute limb ischemia.
It has also been suggested that inorganic iodides act as antioxidants through an ancient direct mechanism. Recently, a computer simulation suggested that iodide may protect against SARS-CoV-2 directly by exhausting the electron donor property of the S protein by acting as a strong electron sink.
There is initial evidence to warrant comprehensive clinical and basic research on the related pathways and possible benefits of iodide for treatment of COVID-19.
Elife. 2019 Nov 26;8:e50276. doi: 10.7554/eLife.50276.
Entry by multiple picornaviruses is dependent on a pathway that includes TNK2, WASL, and NCK1
Hongbing Jiang 1, Christian Leung 1, Stephen Tahan 1, David Wang 1
Comprehensive knowledge of the host factors required for picornavirus infection would facilitate antiviral development. Here we demonstrate roles for three human genes, TNK2, WASL, and NCK1, in infection by multiple picornaviruses. CRISPR deletion of TNK2, WASL, or NCK1 reduced encephalomyocarditis virus (EMCV), coxsackievirus B3 (CVB3), poliovirus and enterovirus D68 infection, and chemical inhibitors of TNK2 and WASL decreased EMCV infection. Reduced EMCV lethality was observed in mice lacking TNK2. TNK2, WASL, and NCK1 were important in early stages of the viral lifecycle, and genetic epistasis analysis demonstrated that the three genes function in a common pathway. Mechanistically, reduced internalization of EMCV was observed in TNK2 deficient cells demonstrating that TNK2 functions in EMCV entry. Domain analysis of WASL demonstrated that its actin nucleation activity was necessary to facilitate viral infection. Together, these data support a model wherein TNK2, WASL, and NCK1 comprise a pathway important for multiple picornaviruses.
J Gen Virol. 2018 May;99(5):619-630. doi: 10.1099/jgv.0.001047. Epub 2018 Mar 20.
Coronavirus S protein-induced fusion is blocked prior to hemifusion by Abl kinase inhibitors
Jeanne M Sisk 1, Matthew B Frieman 2, Carolyn E Machamer 1
Enveloped viruses gain entry into host cells by fusing with cellular membranes, a step that is required for virus replication. Coronaviruses, including the severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV) and infectious bronchitis virus (IBV), fuse at the plasma membrane or use receptor-mediated endocytosis and fuse with endosomes, depending on the cell or tissue type. The virus spike (S) protein mediates fusion with the host cell membrane. We have shown previously that an Abelson (Abl) kinase inhibitor, imatinib, significantly reduces SARS-CoV and MERS-CoV viral titres and prevents endosomal entry by HIV SARS S and MERS S pseudotyped virions. SARS-CoV and MERS-CoV are classified as BSL-3 viruses, which makes experimentation into the cellular mechanisms involved in infection more challenging. Here, we use IBV, a BSL-2 virus, as a model for studying the role of Abl kinase activity during coronavirus infection. We found that imatinib and two specific Abl kinase inhibitors, GNF2 and GNF5, reduce IBV titres by blocking the first round of virus infection. Additionally, all three drugs prevented IBV S-induced syncytia formation prior to the hemifusion step. Our results indicate that membrane fusion (both virus-cell and cell-cell) is blocked in the presence of Abl kinase inhibitors. Studying the effects of Abl kinase inhibitors on IBV will be useful in identifying the host cell pathways required for coronavirus infection. This will provide an insight into possible therapeutic targets to treat infections by current as well as newly emerging coronaviruses.
Mol Cancer Res. 2020 Dec 16;molcanres.0814.2020. doi: 10.1158/1541-7786.MCR-20-0814.
Relevance of the Bruton Tyrosine Kinase (BTK) as a target for COVID-19 therapy
Miran Rada 1, Zahraa Qusairy 2, Marta Massip-Salcedo 3, Salvador Macip 4
The outbreak of the novel coronavirus disease 2019 (COVID-19) has emerged as one of the biggest global health threats worldwide. As of October 2020, over 44 million confirmed cases and more than 1,160,000 deaths have been reported globally, and the toll is likely to be much higher before the pandemic is over. There are currently little therapeutic options available and new potential targets are intensively investigated. Recently, Bruton Tyrosine Kinase (BTK) has emerged as an interesting candidate. Elevated levels of BTK activity have been reported in blood monocytes from patients with severe COVID-19, compared to those from healthy volunteers. Importantly, various studies confirmed empirically that administration of BTK inhibitors (Acalabrutinib and Ibrutinib) decreased the duration of mechanical ventilation and mortality rate for hospitalized patients with severe COVID-19. Herein, we review the current information regarding the role of BTK in SARS-CoV-2 infections and the suitability of its inhibitors as drugs to treat COVID-19. Implications: The use of BTK inhibitors in the management of COVID-19 shows promise in reducing the severity of the immune response to the infection and thus mortality. However, BTK inhibition may be contributing in other ways to inhibit the effects of the virus and this will need to be carefully studied.
Med Hypotheses. 2020 Nov; 144: 110167.
Is there a role for insulin-like growth factor inhibition in the treatment of COVID-19-related adult respiratory distress syndrome?
Bryan J. Winna,b,⁎
Adult respiratory distress syndrome (ARDS) is the leading cause of death associated with SARS-CoV-2 infection and COVID-19. IGF-1 has been implicated in ARDS, yet its role in relation to COVID-19-related lung injury has not been investigated. We hypothesize that blockage of the IGF-1 receptor (IGF-1R) mitigates lung injury and decreases the risk of death in patients COVID-19-related ARDS. Patients with fibroproliferative ARDS have been shown to have increased IGF-1 and IGF-1R staining in lung tissue specimens. Rising levels of IGF-1 in bronchioalveolar fluid (BAL) and increased IGF-1 mRNA expression in lung tissues (but declining serum IGF-1 levels) have been found in late stage ARDS compared with early lung injury. Blockage of IGF-1R decreases lung tissue damage and increases survival in bleomycin-induced as well as H1N1 influenza-related lung injury in animal models. Teprotumumab is a monoclonal antibody directed against the IGF-1R that was FDA-approved in 2020 for the treatment of Graves’ orbitopathy. In order to determine if teprotumumab may reduce lung injury and death related to ARDS in the setting of COVID-19, preliminary clinical data is needed. IGF-1 levels in serum and BAL fluid must be measured in patients with COVID-19-related ARDS. Histopathology from lung samples from patients with COVID-19-related ARDS must be examined for increased expression of the IGF-1R. Once these are ascertained, and if the data support IGF-1 involvement, a randomized, placebo-controlled phase 2A trial of teprotumumab therapy in the setting of COVID-19-related ARDS and non-COVID-19-related ARDS designed to generate initial data on short-term efficacy, safety, dosing and administration should be performed.
PLoS One. 2015; 10(4): e0124651.
A Functional Role of Fibroblast Growth Factor Receptor 1 (FGFR1) in the Suppression of Influenza A Virus Replication
Xin Liu, Chengcai Lai, Keyu Wang, Li Xing, Penghui Yang, Qing Duan, and Xiliang Wang,*
Influenza A virus causes annual epidemics and occasional pandemics in humans. Here, we investigated four members of the fibroblast growth factor receptor (FGFR) family; FGFR1 to 4, and examined their expression patterns in human lung epithelial cells A549 with influenza A virus infection. We identified a functional role of FGFR1 in influenza A/Puerto Rico/8/1934 (PR8) and A/Anhui/01/2005 (H5N1) virus replication. Our results showed that FGFR1 silencing by siRNA interference promoted influenza A/PR8 and H5N1 virus replication in A549 cells, while lentivirus-mediated exogenous FGFR1 expression significantly suppressed influenza A virus replication; however, FGFR4 did not have the same effects. Moreover, FGFR1 phosphorylation levels were downregulated in A549 cells by influenza A virus infection, while the repression of FGFR1 kinase using PD173074, a potent and selective FGFR1 inhibitor, could enhance virus replication. Furthermore, we found that FGFR1 inhibits influenza virus internalization, but not binding, during viral entry. These results suggested that FGFR1 specifically antagonizes influenza A virus replication, probably by blocking viral entry.
Mol Cell. 2020 Oct 1;80(1):164-174.e4. doi: 10.1016/j.molcel.2020.08.006. Epub 2020 Aug 11.
Growth Factor Receptor Signaling Inhibition Prevents SARS-CoV-2 Replication
Kevin Klann, Denisa Bojkova, Georg Tascher, Sandra Ciesek, Christian Münch, Jindrich Cinatl
SARS-CoV-2 infections are rapidly spreading around the globe. The rapid development of therapies is of major importance. However, our lack of understanding of the molecular processes and host cell signaling events underlying SARS-CoV-2 infection hinders therapy development. We use a SARS-CoV-2 infection system in permissible human cells to study signaling changes by phosphoproteomics. We identify viral protein phosphorylation and define phosphorylation-driven host cell signaling changes upon infection. Growth factor receptor (GFR) signaling and downstream pathways are activated. Drug-protein network analyses revealed GFR signaling as key pathways targetable by approved drugs. The inhibition of GFR downstream signaling by five compounds prevents SARS-CoV-2 replication in cells, assessed by cytopathic effect, viral dsRNA production, and viral RNA release into the supernatant. This study describes host cell signaling events upon SARS-CoV-2 infection and reveals GFR signaling as a central pathway essential for SARS-CoV-2 replication. It provides novel strategies for COVID-19 treatment.