Frontier | Research progress of kinase inhibitors in the treatment of coronavirus infections
July 19, 2021
As of now, the cumulative number of COVID-19 infections worldwide has exceeded 187 million, and about 4 million have died (Figure 1). Although relevant vaccines have already been put into vaccination, the growth rate of cumulative global cases has slowed down overall, and local growth has been relatively rapid (South America). But when the epidemic will end is not yet known. In particular, the emergence of various virus mutant strains has made the situation more complicated and changeable. Therefore, vaccination is one aspect, and the development of anti-coronavirus drugs is still urgent.
Figure 1. Cumulative COVID-19 cases from 2020.5.1 to 2021.7.6: the number of infections per million people (https://ourworldindata.org/covid-cases)
1 Introduction
COVID-19 is a potentially fatal respiratory infection caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). The virus genome structure is highly similar to the previous SARS-CoV-1 genome structure (genetic similarity) Is 79%). Studies have found that in addition to directly targeting viral proteins, some host proteins are also potential targets for anti-coronavirus therapy, such as host kinases. These kinases not only play an important role in the virus infection cycle (enter, replicate, assemble, and leave), but also participate in the excessive inflammatory response induced by the virus, leading to cytokine storm, acute respiratory distress syndrome (ARDS), organ injury and even death. Recently, Stefan Laufer published a review article in the Journal of Medicinal Chemistry, introducing the kinases associated with coronavirus infection and the research progress of these kinase inhibitors for anti-coronavirus.
2 Development of kinase inhibitors
Among all host components, kinases can play a role in all stages of the virus life cycle. Studies have shown that kinases are potential mediators of a variety of viral infections (Table 1).
Table 1. The role of kinases in coronavirus infections
2.1 Abl and Src kinase inhibitors
Abl kinase is a ubiquitous signal kinase that plays a role in cell proliferation, adhesion and stress response. Dyall et al. found that Imatinib and Dasatinib are active against SARS-CoV-1 and MERS-CoV, while Nilotinib is only active against SARS-CoV-1 ( figure 2). Cathepsin L (Cathepsin L) and transmembrane serine protease 2 (TMPRSS2) play a vital role in virus entry; studies have found that inhibiting cathepsin L can prevent SARS-CoV-1 infection, and use EST (a tissue A mixture of protease inhibitors) and Camostat (a serine protease inhibitor, Figure 2) can completely prevent virus entry and replication.
2.2 Src family kinase inhibitors
Src family kinases (SFK) are key regulators of signal transduction and are non-receptor tyrosine kinases. There are nine members in this family: Src, Yes, Fyn, Fgr, Lck, Hck, Blk, Lyn and Yrk. Src kinase participates in vaccinia virus replication by activating Abl kinase. Research by De Wispelaere et al. showed that dasatinib and Saracatinib (Figure 3) can inhibit dengue virus assembly.
Figure 2. Abl tyrosine kinase and Src kinase inhibitors as antiviral agents (Imatinib: SARS-CoV-1, EC50 9.823 M, MERS-CoV, EC50 2.100 M; Dasatinib: SARS-CoV- 1, EC50 17.689 M, MERS-CoV, EC50 5.468 μM)
2.3 Numb-related kinase (NAK) family and AXL kinase inhibitors
The Numb-related Ser/Ther kinase family plays a vital role in the replication of many viruses. Two of the homologs AAK1 and GAK are related to the entry, assembly and release of viruses such as dengue fever, HCV, Ebola, SARS-CoV-1 and -2, and MERS-CoV. Sunitinib and Erlotinib can inhibit AAK1 and GAK, and show antiviral effects on dengue fever and Ebola virus in cultured cells. Baricitinib is an inhibitor of Janus kinase-1 (JAK-1) and JAK-2. It has been approved by the FDA for the treatment of patients with moderate to severe rheumatoid arthritis. The new study found that the drug is also a potential inhibitor of SARS-CoV-2 activity. In November 2020, the U.S. FDA approved an emergency use authorization (EUA) for Baricitinib combined with Remdesivir to treat the new coronavirus (Figure 3).
Figure 3. NAK family inhibitors (sunitinib, erlotinib, and Baricitinib are used to treat coronavirus infections)
Figure 4. Baricitinib inhibits JAK1, thereby preventing SARS-CoV-2 from entering and ARD
A number of clinical trials of Baricitinib monotherapy and combination therapy are currently underway to verify its antiviral activity (Table 2).
Table 2. Clinical trials of Baricitinib for the treatment of COVID-19
2.4 AXL inhibitor
AXL is a tyrosine kinase on the cell surface that controls cell replication, growth, differentiation and immunity. Inhibition of AXL leads to a decrease in inhibitors of cytokine signaling-1 (SOCS1) and SOCS3 proteins, increases the expression of IFNγ, and reduces viral replication. According to reports, the AXL inhibitor Gilteritinib (Figure 5) has an IC50 value of 0.807 μM for inhibiting SARS-CoV-2 replication in cell experiments.
Figure 5. The IC50 of AXL kinase inhibitor Gilteritinib for SARS-CoV-2 inhibition is 0.807 M)
2.5 EGFR signaling pathway inhibitor
Epidermal growth factor receptor (EGFR) is a prototype tyrosine kinase (RTK) receptor. Osimertinib is reported to be an effective inhibitor of SARS-CoV-2 S protein (EC50 3.98 μM) (Figure 8).
Figure 6. Osimertinib
2.6 PI3K/Akt/mTOR pathway inhibitor
Klann et al. confirmed that PI3K inhibitor Pictilisib (IC50 2.58 μM) and PI3K/mTOR dual inhibitor Omipalisib (IC50 0.014 μM) can inhibit SARS-CoV-2 virus replication in cells (Figure 7). In addition, dual RAF/MEK inhibitors Sorafenib (IC50 4.85 μM) and RO5126766 (IC50 0.6 μM) can also block virus replication. In addition, Lonafarnib, Everolimus, Miltefosine, Wortmannin, and Rapamycin may also inhibit SARS-CoV-2 or MERS-CoV viruses (Figure 7).
Figure 7. PI3K/Akt/mTOR pathway inhibitors with SARS-CoV-2 or MERS-CoV inhibitory activity
2.7 Other kinase inhibitors with coronavirus inhibitory effect
In addition to the above-mentioned kinase inhibitors, cyclin-dependent kinase (CDK) inhibitors and casein kinase 2 inhibitors also show certain coronavirus inhibitory activity (Figure 8).
Figure 8. Other kinase inhibitors with corona virus inhibitory effect
3 Development of kinase pathway inhibitors
In addition to participating in the virus life cycle, many kinases also play a role in the progression of symptoms such as pneumonia, inflammation, and fibrosis associated with coronavirus infection. Studies believe that SARS-CoV-1 will inhibit the activity of ACE2 and thereby inhibit the production of angiotensin I (Ang1-7), which in turn activates the p38 MAPK pathway in the lung and heart, leading to increased expression of inflammatory responses (Figure 9). In addition, p38 MAPK activation up-regulates ADAM17, further reducing the supply of ACE2 activity. Therefore, ACE2 inhibitors or ACE blockers that balance the renin-angiotensin system may be useful for the treatment of COVID-19.
Figure 9. The role of p38 MAPK and its interaction with other signaling pathways and inflammatory cytokines
In addition to the p38 MAPK signaling pathway, the signaling pathways of JAK-STAT and glycogen synthase kinase 3 (GSK-3) are also involved in related inflammatory responses. Therefore, inhibitors targeting these pathways may also have a positive effect on the treatment of coronavirus infections.
4 summary
Studies have shown that a variety of inhibitors targeting kinases have antiviral activity. At present, products such as Baricitinib have been approved for marketing, and there are many potential drugs in phase I-III clinical studies. However, when these kinase inhibitors are used to treat COVID-19, it is also necessary to consider their adverse reactions and pharmacokinetic properties. In addition, combination therapy may be a trend, and the advantages of combination therapy have been shown in the treatment of diseases such as HIV. Therefore, antiviral drugs (ribavirin, ritonavir-lopinavir, remdesivir) and kinase inhibitors (sunitinib, erlotinib, sorafenib, imatinib) , Gilteritinib, gilteritinib, osimertinib) or the combined use of kinase inhibitors targeting virus-related proteins and lung health-related proteins may be beneficial to the treatment of related diseases.
references
Pillaiyar, Thanigaimalai, and Stefan Laufer. "Kinases as Potential Therapeutic Targets for Anti-coronaviral Therapy." Journal of Medicinal Chemistry (2021).
