Stenoparib, an inhibitor of cellular poly (ADP-ribose) polymerases (PARPs), blocks in vitro replication of SARS-CoV-2 variants

Abstract

AbstractWe 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 μM, 8.5 μM, 24.2 μM and 13.6 μM, respectively. A second study focusing on a combination of 10 μM stenoparib and 0.5 μM 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.ImportanceThe coronavirus disease (COVID-19) pandemic, caused by SARS-CoV-2, has caused over 247 million infections and over 5 million deaths (1). Although protective vaccines are available, the pandemic continues and both old and new SARS-CoV-2 variants may exhibit degrees of resistance to vaccination. To date, only two antiviral drugs, remdesivir and molnupiravir, or treatment with monoclonal antibodies, have been approved by the United States Food and Drug Administration as COVID-19 therapies in certain situations. Additional effective therapeutics are urgently needed. Here we describe the activity of a small molecule, stenoparib, that effectively inhibits replication of SARS-CoV-2 wild-type and variant strains in vitro. Stenoparib is an inhibitor of mammalian poly (ADP-ribose) polymerases (PARPs). A host-targeting therapeutic like stenoparib could be a significant benefit for COVID-19 patients as a standalone therapy, or especially as part of a combinatorial COVID-19 treatment strategy with an antiviral drug such as remdesivir or molnupiravir.