Stenoparib, an inhibitor of cellular poly (ADP-ribose) polymerase (PARP), blocks replication of the SARS-CoV-2 human coronavirus in vitro

Abstract By late 2020, the coronavirus disease (COVID-19) pandemic, caused by SARS-CoV-2 has caused tens of millions of infections and over 1 million deaths worldwide. A protective vaccine and more effective therapeutics are urgently needed. We evaluated a new PARP inhibitor, stenoparib, for which was recently advanced to Stage II clinical trials for treatment of ovarian cancer. This is an initial report on the activity of stenoparib against human respiratory coronaviruses, including SARS-CoV-2, in vitro. Stenoparib exhibits dose-dependent suppression of SARS-CoV-2 multiplication and spread in Vero E6 monkey kidney and Calu-3 human lung adenocarcinoma cells. Stenoparib was also strongly inhibitory to multiplication of the HCoV-NL63 human seasonal respiratory coronavirus. Compared to remdesivir, which inhibits the viral replicon subsequent to cell entry, stenoparib is inhibitory to virus entry and post-entry processes as determined by time-of-addition (TOA) experiments. Moreover, a 10 μM dosage of stenoparib, which is far below its 25.5 μM half-maximally effective concentration (EC50), when combined with 0.5 μM remdesivir suppressed coronavirus growth by 90.7%, indicating a potentially synergistic effect for this drug combination. Thus, stenoparib as a standalone or as a component of combinatorial therapy with remdesivir may be a valuable addition to the arsenal against COVID-19. Importance New therapeutics are urgently needed in the fight against COVID-19. Repurposing drugs that are either already approved for human use or are in advanced stages of the approval process can facilitate more rapid advances toward this goal. The PARP inhibitor stenoparib may be such a drug, as it is currently in Stage II clinical trials for the treatment of ovarian cancer and its safety and dosage in humans has already been established. Our results indicate that stenoparib possesses strong antiviral activity against SARS-CoV-2 and other coronaviruses in vitro. This activity appears to be based on multiple modes of action, where both pre-entry and post-entry viral replication processes are impeded. This may provide a therapeutic advantage over many current options that have a narrower target range. Moreover, our results suggest that stenoparib and remdesivir may be an especially potent combination against coronavirus infection.