In February 2020 as the SARS-CoV-2 outbreak began in the USA, we initiated a range of collaborations with scientists around the world with the goal of identifying new molecules with antiviral activity. We had previously identified three molecules (pyronaridine tetraphosphate, tilorone and quinacrine) for Ebola using machine learning approaches and we prioritized these for in vitro testing. We were faced with the challenge that the in vitro assays all used Vero cells infected with SARS-CoV-2. It was not until later in the year when we were able to test in mammalian cells lines such as A549-ACE2 that we demonstrated these compounds had similar nM activity as remdesivir. Pyronaridine treatment demonstrated a statistically significant reduction of viral load in the lungs of SARS CoV-2 infected mice, reduced lung pathology, which was also associated with significant reduction in the levels of pro-inflammatory cytokines/chemokine and cell infiltration. Pyronaridine also inhibited the viral PLpro activity (IC50 of 1.8 µM) and this led to the design and exploration of this structural activity relationship. We also identified bosutinib, crizotinib and olmutinib with activity against PLpro and vandetanib with in vitro activity against SARS-CoV-2. The in vivo efficacy of vandetanib was assessed in a mouse model of SARS-CoV-2 infection and statistically significantly reduced the levels of IL-6, IL-10, TNF-α, and mitigated inflammatory cell infiltrates in the lungs of infected animals but did not reduce viral load. These molecules also suggest some potential use for addressing the COVID induced cytokine storm even if antiviral activity is observed. We went to some efforts to curate the accumulating in vitro data and use it for building and validating different machine learning models including quantum machine learning. Perhaps our biggest accomplishment was to encourage a South Korean pharmaceutical company to undertake a clinical trial with Pyramax (pyronaridine and artesunate), which is now in Phase III trials. There are still challenges for the future such as the need to find treatments for the millions affected by long COVID which is not addressed by any existing treatments and may require further collaborations. 2 years on and we are ready to address the next pandemic virus with our collaborator network and integrated approaches.

Integrating computational, in vitro and in vivo approaches for SARS-CoV-2 drug discovery

Fall 2022 abstracts, posters, and presentations will launch in mid-September.

ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.