Targeting of Protein Kinase CK2 Elicits Antiviral Activity on Bovine Coronavirus Infection (preprint)

Coronaviruses constitute a global threat to human population since three highly pathogenic coronaviruses (SARS-CoV, MERS-CoV and SARS-CoV-2) have crossed species to cause severe human respiratory disease. Considering the worldwide emergency status due to the current COVID-19 pandemic, effective pan-coronavirus antiviral drugs are required to tackle the ongoing as well as future (re)emerging virus outbreaks. Protein kinase CK2 has been deemed a promising therapeutic target in COVID-19 supported by its in vitro pharmacologic inhibition and molecular studies on SARS-CoV-2 infected cells. CIGB-325 is a first-in-class synthetic peptide impairing the CK2-mediated signaling whose safety and clinical benefit have been evidenced in Covid-19 and cancer patients after intravenous administration. Here, we explored the putative antiviral effect of CIGB-325 over MDBK cells infected by bovine coronavirus (BCoV) Mebus. Importantly, CIGB-325 inhibited both the cytopathic effect and the number of plaques forming units with a half-inhibitory concentrations IC50 = 3.5 uM and 17.7 uM, respectively. Accordingly, viral protein accumulation at the cytoplasm was clearly reduced by treating BCoV-infected cells with CIGB-325 over time, as determined by immunocytochemistry. Of note, data from pull-down assay followed by western blot and/or mass spectrometry identification revealed physical interaction of CIGB-325 with nucleocapsid (N) protein and a bona fide cellular CK2 substrates. Functional enrichment and network analysis from the CIGB-325 interacting proteins indicated cytoskeleton reorganization and protein folding as the most represented biological processes disturbed by this anti-CK2 peptide. Altogether, our findings not only unveil the direct antiviral activity of CIGB-325 on coronavirus infection but also provide molecular clues underlying such effect. Also, our data reinforce the scientific rationality behind the pharmacologic inhibition of CK2 to treat coronavirus infections.

Treatment with an Anti-CK2 Synthetic Peptide Improves Clinical Response in Covid-19 Patients with Pneumonia. A Randomized and Controlled Clinical Trial (preprint)

PurposeThe instrumental role of CK2 in the SARS-Cov2 infection has pointed out this protein kinase as a promising therapeutic target in Covid-19. Anti-SARS-Cov2 activity has been reported by CK2 inhibitors in vitro; however, any anti-CK2 clinical approach has been investigated in Covid-19. This exploratory trial aimed to explore safety and putative clinical benefit of CIGB-325, an anti-CK2 peptide previously assessed in cancer. MethodsA monocentric, parallel group design, therapeutic exploratory trial of intravenous CIGB-325 in adults hospitalized with Covid-19 was performed. Twenty patients were randomly assigned to receive CIGB-325 (2.5 mg/kg/day during 5-consecutive days) plus standard-of-care (10 patients) or standard-of-care (10 patients). Adverse events were classified by the WHO Adverse Reaction Terminology. Parametric and non-parametric statistical analyses were performed according to the type of variable. Considering the small sample size, differences between groups were estimated by Bayesian analysis. FindingsCIGB-325 induced transient mild and/or moderate adverse events like pruritus, flushing and rash in some patients. Both therapeutic regimens were similar respect to SARS-Cov2 clearance in nasopharynx swabs over the time. However, CIGB-325 significantly reduced the median number of pulmonary lesions (9.5 to 5.5, p = 0.042) at day 7 and proportion of patients with such effect was also higher according to Bayesian analysis (pDif > 0; 0.951). Additionally, CIGB-325 significantly reduced the CPK (p = 0.007) and LDH (p = 0.028) plasma levels at day 7. ImplicationsOur preliminary findings suggest that this anti-CK2 clinical approach could be combined with standard-of-care in Covid-19 thus warranting larger studies.