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.

Functional antibody and T cell immunity following SARS-CoV-2 infection, including by variants of concern, in patients with cancer: the CAPTURE study.

Patients with cancer have higher COVID-19 morbidity and mortality. Here we present the prospective CAPTURE study, integrating longitudinal immune profiling with clinical annotation. Of 357 patients with cancer, 118 were SARS-CoV-2 positive, 94 were symptomatic and 2 died of COVID-19. In this cohort, 83% patients had S1-reactive antibodies and 82% had neutralizing antibodies against wild type SARS-CoV-2, whereas neutralizing antibody titers against the Alpha, Beta and Delta variants were substantially reduced. S1-reactive antibody levels decreased in 13% of patients, whereas neutralizing antibody titers remained stable for up to 329 days. Patients also had detectable SARS-CoV-2-specific T cells and CD4+ responses correlating with S1-reactive antibody levels, although patients with hematological malignancies had impaired immune responses that were disease and treatment specific, but presented compensatory cellular responses, further supported by clinical recovery in all but one patient. Overall, these findings advance the understanding of the nature and duration of the immune response to SARS-CoV-2 in patients with cancer.

Consensus minimum hemoglobin level above which patients with myelodysplastic syndromes can safely forgo transfusions.

The anemia of MDS often results in decreased quality of life, which is invoked to justify red cell transfusions; however, there are sparse data regarding the minimum hemoglobin (Hb) at which it is safe to forgo transfusions for patients with no evidence of end-organ damage. This issue is even more important in the COVID-19 era, where decreases in blood donations have stressed the blood supply. In March 2018, using a modified Delphi method, we convened a panel of 13 expert MDS clinicians for three iterative rounds to discuss a minimum safe Hb for this population. While the panel was unable to reach the pre-set consensus of 75% for a specific Hb threshold, there was 100% consensus that it be no greater than 7.5 g/dL. Our data suggest that, given no end-organ effects of anemia, patients with MDS can safely forgo transfusions with a Hb of 7.5 g/dL or higher.

Iran confronts coronavirus amid a ‘battle between science and conspiracy theories’

When Mehdi Variji fell ill with COVID-19 in early March, he holed up in his apartment in Tehran to ride it out. The comforts of home didn’t seem to help. As he grew short of breath and oxygen levels in his blood ebbed, Variji, a 43-year-old physician who ran Tehran’s 21st District Clinic, knew he faced a bleak prognosis. “I’m taking three medicines, but they are not working on me,” he said in a cellphone video he shot a few days before his death. A somber cell-phone video shot on 20 March shows four gowned and masked workers preparing his grave in the courtyard of a shrine in his hometown, Sari. His wife and children stayed away because of the infection risk. It was just after midnight on Nowruz, the first day of the Persian new year and normally the beginning of a joyous festival.

The new coronavirus is finally slamming Russia. Is the country ready?

For weeks, Russia seemed to have dodged a bullet. As coronavirus disease 2019 (COVID-19) raged just across the border in China, Russia was virtually untouched, reporting just seven confirmed infections as recently as 10 March. Since then, the number has risen fast: Russia has now reported 840 infections, about two-thirds of them in the Moscow region.

Coronavirus disruptions could hurt North Korea’s efforts to treat tuberculosis

North Korea watchers warn that the country’s aggressive measures to defend itself against COVID-19, the illness caused by the novel coronavirus, are hobbling efforts to combat tuberculosis (TB) and other infectious diseases. Sandwiched between two COVID-19 hot spots—China and South Korea—North Korea at the end of January suspended international flights and severed its rail link with China. Since then, cargo containers headed to North Korea’s port in Nampo have stalled in Dalian, China, snagged on red tape in China and new quarantine procedures in Nampo. The only way in and out of North Korea now is a road crossing on its northern border with China. North Korea’s state media has said the border restrictions will remain in effect until COVID-19 has stopped spreading or a vaccine is available. That puts North Korea’s thousands of TB patients in a precarious situation. Three containers with first-line TB drugs are among hundreds held up in Dalian, says a U.S.-based humanitarian organization official, who requested anonymity. The official notes that North Korea’s supply of first-line TB drugs is expected to run out in May or June. The situation is even more perilous for North Koreans infected with multidrug-resistant TB strains. Treatment lapses can lead to even more recalcitrant strains. “Truly it opens grave concern” about the development of extensively drug-resistant TB in North Korea, the official says. Related