Recent Developments in the Use of Kinase Inhibitors for Management of Viral Infections

Abstract

Kinases are a group of therapeutic targets involved in the progression of numerous diseases, including cancer, rheumatoid arthritis, Alzheimer's disease, and viral infections. The majority of approved antiviral agents are inhibitors of virusspecific targets that are encoded by individual viruses. These inhibitors are narrow-spectrum agents that can cause resistance development. Viruses are dependent on host cellular proteins, including kinases, for progression of their life-cycle. Thus, targeting kinases is an important therapeutic approach to discovering broadspectrum antiviral agents. As there are a large number of FDA approved kinase inhibitors for various indications, their repurposing for viral infections is an attractive and time-sparing strategy. Many kinase inhibitors, including baricitinib, ruxolitinib, imatinib, tofacitinib, pacritinib, zanubrutinib, and ibrutinib, are under clinical investigation for COVID-19. Herein, we discuss FDA approved kinase inhibitors, along with a repertoire of clinical/ preclinical stage kinase inhibitors that possess antiviral activity or are useful in the management of viral infections.

System-oriented optimization of multi-target 2,6-diaminopurine derivatives: Easily accessible broad-spectrum antivirals active against flaviviruses, influenza virus and SARS-CoV-2

“…Despite potent nanomolar kinase inhibitors with no antiviral activity have been reported among 2,6-diaminopurine derivatives, [ 61 ] our compounds showed a moderate inhibitory effect on the selected kinases at micromolar concentration: in particular, compound 6i reduced the activity of Src, Abl and PI3Kα by roughly 50% at 5 μM. The get a wider picture on the kinase specificity of 6i , it was also tested against an additional panel of 15 host kinases selected among those known from the literature to be involved in the replication of different viruses ( Table S3 , Supporting Information) [ 74 ]. However, no significant inhibition of these additional targets was found testing 6i at 5 μM concentration, making Src, Abl and PI3Kα the only kinases (among the few selected) that are mildly inhibited by our lead compound.…”

Kinases as Potential Therapeutic Targets for Anti-coronaviral Therapy

“…Raghuvanshi and Bharate discussed how kinase inhibitors have recently been developed to treat various viral infections. 49 They primarily focused on different stages of kinase inhibitors as FDA approved, clinical candidates and on discovery that targeted various virus infections, but they did not discuss kinase inhibitors that target human coronaviruses to date. Several research groups reviewed the critical function of different host kinases in influenza A virus infection.…”

Bithiazole Inhibitors of Phosphatidylinositol 4‐Kinase (PI4KIIIβ) as Broad‐Spectrum Antivirals Blocking the Replication of SARS‐CoV‐2, Zika Virus, and Human Rhinoviruses

“…In addition, antiviral drugs targeting host kinases are expected to: i) retain activity against viral mutants resistant to conventional antiviral drugs; ii) minimize drug escape, since host proteins are genetically stable; iii) be active against viruses belonging to different virus families that rely on the same kinase, resulting in broad‐spectrum antiviral agents (BSAAs) which are also useful for outbreaks of newly emerged viruses. So far, a number of host kinases have been identified as promising targets for the development or repurposing of kinase inhibitors as antiviral agents: as reported in a recently published review, kinase inhibitors block the replication of many viruses by interfering with different steps of the viral replication cycle [4] . In particular, phosphatidylinositol kinases (PIKs) play a key role in the formation of replication organelles (ROs), which are the central hub for positive‐strand RNA virus (+RNA virus) replication and protect the viral genome from host defenses [5–7] .…”

“…So far, a number of host kinases have been identified as promising targets for the development or repurposing of kinase inhibitors as antiviral agents: as reported in a recently published review, kinase inhibitors block the replication of many viruses by interfering with different steps of the viral replication cycle. [4] In particular, phosphatidylinositol kinases (PIKs) play a key role in the formation of replication organelles (ROs), which are the central hub for positive‐strand RNA virus (+RNA virus) replication and protect the viral genome from host defenses. [ 5 , 6 , 7 ] Among the different lipid kinases responsible for the conversion of phosphatidylinositols (PI) into phosphoinositides (PPIns) needed for cellular processes, the PI3 K, PI4 K, PIP5KI, and PIKfyve families are those exploited by several viruses (e. g. SARS, MERS, EBOV, HCV, enteroviruses and rhinoviruses, HIV‐1) for entry or replication in cells.…”