Rejuveinix Mitigates Sepsis-Associated Oxidative Stress in the Brain of Mice: Clinical Impact Potential in COVID-19 and Nervous System Disorders (preprint)

Here, we demonstrate that our anti-sepsis and COVID-19 drug candidate Rejuveinix (RJX) substantially improves the survival outcome in the LPS-GalN animal model of sepsis and multi-organ failure. One hundred (100) percent (%) of untreated control mice remained alive throughout the experiment. By comparison, 100% of LPS-GalN injected mice died at a median of 4.6 hours. In contrast to the invariably fatal treatment outcome of vehicle-treated control mice, 40% of mice treated with RJX (n=25) remained alive with a 2.4-fold longer median time survival time of 10.9 hours (Log-rank X2=20.60, P<0.0001). Notably, RJX increased the tissue levels of antioxidant enzymes SOD, CAT, and GSH-Px, and reduced oxidative stress in the brain. These findings demonstrate the clinical impact potential of RJX as a neuroprotective COVID-19 and sepsis drug candidate.

Hydroxyzine inhibits SARS-CoV-2 Spike protein binding to ACE2 in a qualitative in vitro assay (preprint)

COVID-19 currently represents a major public health problem. Multiple efforts are being performed to control this disease. Vaccinations are already in progress. However, no effective treatments have been found so far. The disease is caused by the SARS-CoV-2 coronavirus that through the Spike protein interacts with its cell surface receptor ACE2 to enter into the host cells. Therefore, compounds able to block this interaction may help to stop disease progression. In this study, we have analyzed the effect of compounds reported to interact and modify the activity of ACE2 on the binding of the Spike protein. Among the compounds tested, we found that hydroxyzine could inhibit the binding of the receptor-binding domain of Spike protein to ACE2 in a qualitative in vitro assay. This finding supports the reported clinical data showing the benefits of hydroxyzine on COVID-19 patients, raising the need for further investigation into its effectiveness in the treatment of COVID-19 given its well-characterized medical properties and affordable cost.

Identification of novel antiviral drug combinations in vitro and tracking their development (preprint)

Combination therapies have become a standard for the treatment for HIV and HCV infections. They are advantageous over monotherapies due to better efficacy and reduced toxicity, as well as the ability to prevent the development of resistant viral strains and to treat viral co-infections. Here, we identify several new synergistic combinations against emerging and re-emerging viral infections in vitro. We observed synergistic activity of nelfinavir with investigational drug EIDD-2801 and convalescent serum against SARS-CoV-2 infection in human lung epithelial Calu-3 cells. We also demonstrated synergistic activity of vemurafenib combination with emetine, homoharringtonine, gemcitabine, or obatoclax against echovirus 1 infection in human lung epithelial A549 cells. We also found that combinations of sofosbuvir with brequinar and niclosamide were synergistic against HCV infection in hepatocyte derived Huh-7.5 cells, whereas combinations of monensin with lamivudine and tenofovir were synergistic against HIV-1 infection in human cervical TZM-bl cells. Finally, we present an online resource that summarizes novel and known antiviral drug combinations and their developmental status. Overall, the development of combinational therapies could have a global impact improving the preparedness and protection of the general population from emerging and re-emerging viral threats.

Screening of FDA-approved drugs using a MERS-CoV clinical isolate from South Korea identifies potential therapeutic options for COVID-19 (preprint)

In 2015, the Middle East Respiratory Syndrome Coronavirus (MERS-CoV) reached the Republic of Korea through nosocomial transmission and was the largest epidemic outside of the Arabian Peninsula. To date, despite various strategies to identify CoV interventions, only limited therapeutic options are available. To address these unmet medical needs, we used a South Korean MERS-CoV clinical isolate and screened 5,406 compounds, including United States Food and Drug Administration (FDA)-approved drugs and bioactive molecules, for their activity against the isolate. The primary assay confirmed 221 hits by dose-response curve analysis and identified 54 hits with a therapeutic index (TI) greater than 6. Time-of-addition studies with 12 FDA-approved drugs demonstrated that 8 and 4 therapeutics act on the early and late stages of the viral life cycle, respectively. Among the drugs were e.g., three cardiotonic agents (ouabain, digitoxin, digoxin) with a TI greater than 100, an anti-malaria drug (atovaquone; TI >34), an inhalable corticosteroid (ciclesonide; TI >6), etc. Together, our results identify potential therapeutic options for treating MERS-CoV infections and could provide a basis for agents against a wider range of coronavirus-related illnesses, including the currently emerging Coronavirus Disease 2019 (COVID-19) outbreak.