ABSTRACT
We recently published a preliminary assessment of the activity of a poly (ADP-ribose) polymerase (PARP) inhibitor, stenoparib, also known as 2X-121, which inhibits viral replication by affecting pathways of the host. Stenoparib is an inhibitor of mammalian poly (ADP-ribose) polymerases (PARPs). Here we show that stenoparib effectively inhibits additional SARS-CoV-2 variants, including an additional wild-type strain (Germany/BavPat1/2020), and the variants alpha (B.1.1.7), beta (B.1.351) and gamma (P.1) in vitro, with 50% effective concentration (EC50) estimates of 4.1 M, 8.5 M, 24.2 M and 13.6 M, respectively. A second study focusing on a combination of 10 M stenoparib and 0.5 {micro}M remdesivir resulted in over 90% inhibition of the alpha (B.1.1.7) variant, which is substantially greater than what was achieved with stenoparib or remdesivir alone at these concentrations.
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, 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 M dosage of stenoparib, which is far below its 25.5 M half-maximally effective concentration (EC50), when combined with 0.5 M 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.