Anti-SARS-CoV-2 activity of targeted kinase inhibitors: Repurposing clinically available drugs for COVID-19 therapy.

Coronavirus disease 2019 (COVID-19) remains a major public health concern, and vaccine unavailability, hesitancy, or failure underscore the need for discovery of efficacious antiviral drug therapies. Numerous approved drugs target protein kinases associated with viral life cycle and symptoms of infection. Repurposing of kinase inhibitors is appealing as they have been vetted for safety and are more accessible for COVID-19 treatment. However, an understanding of drug mechanism is needed to improve our understanding of the factors involved in pathogenesis. We tested the in vitro activity of three kinase inhibitors against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), including inhibitors of AXL kinase, a host cell factor that contributes to successful SARS-CoV-2 infection. Using multiple cell-based assays and approaches, gilteritinib, nintedanib, and imatinib were thoroughly evaluated for activity against SARS-CoV-2 variants. Each drug exhibited antiviral activity, but with stark differences in potency, suggesting differences in host dependency for kinase targets. Importantly, for gilteritinib, the amount of compound needed to achieve 90% infection inhibition, at least in part involving blockade of spike protein-mediated viral entry and at concentrations not inducing phospholipidosis (PLD), approached a clinically achievable concentration. Knockout of AXL, a target of gilteritinib and nintedanib, impaired SARS-CoV-2 variant infectivity, supporting a role for AXL in SARS-CoV-2 infection and supporting further investigation of drug-mediated AXL inhibition as a COVID-19 treatment. This study supports further evaluation of AXL-targeting kinase inhibitors as potential antiviral agents and treatments for COVID-19. Additional mechanistic studies are needed to determine underlying differences in virus response.

Risk Factors for Actinic Keratoses: A Systematic Review and Meta-Analysis.

Objective: To integrate evidence and assess the risk factors associated with actinic keratosis (AK). Methods: Unrestricted searches were conducted on five electronic databases, with an end-date parameter of September 2021. We summarized the study characteristics and pooled the results from individual studies by using a random-effects model. The risk of bias was estimated using the Cochrane Risk of Bias Tool, and the quality of evidence was estimated according to the Newcastle-Ottawa Scale. Results: Sixteen studies were included in final analysis, and we assessed the AK risk among a variety of risk factors. Overall, the male sex (odds ratio (OR): 2.51; 95% confidence interval (CI): 1.94-3.25; P < 0.01), age >45 years (OR = 7.65, 95% CI: 2.95-19.86; P < 0.01), light Fitzpatrick skin phototype (OR = 2.32, 95% CI: 1.74-3.10; P < 0.01), light hair color (OR = 2.17, 95% CI: 1.40-3.36; P < 0.01), light eye color (OR = 1.67, 95% CI: 1.03-2.70; P = 0.04), freckles on face/arms (OR = 1.88, 95% CI: 1.37-2.58; P < 0.01), suffered positive history of other types of non-melanoma skin cancer (OR = 4.46, 95% CI: 2.71-7.33; P < 0.01), sunburns in childhood (OR = 2.33, 95% CI: 1.47-3.70; P < 0.01) and adulthood (OR = 1.50, 95% CI: 1.12-2.00; P < 0.01), severe sunburn (OR = 1.94, 95% CI: 1.62-2.31; P < 0.01), and chronic occupational and/or recreational sun exposure (OR = 3.22, 95% CI: 2.16-4.81; P < 0.01) increased the risk of AK. Moreover, sunscreen use (OR = 0.51, 95% CI: 0.34-0.77; P < 0.01) and history of atopy reduced the risk of AK. Sensitivity analysis yielded consistent results. The included studies showed a high risk of bias. Conclusion: We confirm several well-known AK risk factors and their quantitative data, and summarized the uncommon risk factors and protective factors. Our results may inform on the design and implementation of AK screening and educational programs.

The comprehensive study on the therapeutic effects of baicalein for the treatment of COVID-19 in vivo and in vitro.

Baicalein is the main active compound of Scutellaria baicalensis Georgi, a medicinal herb with multiple pharmacological activities, including the broad anti-virus effects. In this paper, the preclinical study of baicalein on the treatment of COVID-19 was performed. Results showed that baicalein inhibited cell damage induced by SARS-CoV-2 and improved the morphology of Vero E6 cells at a concentration of 0.1 µM and above. The effective concentration could be reached after oral administration of 200 mg/kg crystal form ß of baicalein in rats. Furthermore, baicalein significantly inhibited the body weight loss, the replication of the virus, and relieved the lesions of lung tissue in hACE2 transgenic mice infected with SARS-CoV-2. In LPS-induced acute lung injury of mice, baicalein improved the respiratory function, inhibited inflammatory cell infiltration in the lung, and decreased the levels of IL-1ß and TNF-α in serum. In conclusion, oral administration of crystal form ß of baicalein could reach its effective concentration against SARS-CoV-2. Baicalein could inhibit SARS-CoV-2-induced injury both in vitro and in vivo. Therefore, baicalein might be a promising therapeutic drug for the treatment of COVID-19.

Repurposing of Kinase Inhibitors for Treatment of COVID-19.

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.