Stenoparib, an Inhibitor of Cellular Poly(ADP-Ribose) Polymerase, Blocks Replication of the SARS-CoV-2 and HCoV-NL63 Human Coronaviruses In Vitro.

Abstract

By late 2020, the coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), had 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 poly(ADP-ribose) polymerase (PARP) inhibitor, stenoparib, that recently advanced to phase II clinical trials for treatment of ovarian cancer, for activity 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 the human seasonal respiratory coronavirus HCoV-NL63. Compared to remdesivir, which inhibits viral replication downstream of cell entry, stenoparib impedes entry and postentry processes, as determined by time-of-addition (TOA) experiments. Moreover, a 10 μM dosage of stenoparib-below the approximated 25.5 μM half-maximally effective concentration (EC50)-combined with 0.5 μM remdesivir suppressed coronavirus growth by more than 90%, indicating a potentially synergistic effect for this drug combination. Stenoparib as a stand-alone or as part of combinatorial therapy with remdesivir should 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 phase II clinical trials for the treatment of ovarian cancer and its safety and dosage in humans have 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 postentry 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 in combination may be especially potent against coronavirus infection.

• Authors: Nathan E Stone, Sierra A Jaramillo, Ashley N Jones, Adam J Vazquez, Madison Martz, Lora M Versluis, Marlee O Raniere, Haley E Nunnally, Katherine E Zarn, Roxanne Nottingham, Ken R Ng, Jason W Sahl, David M Wagner, Steen Knudsen, Erik W Settles, Paul Keim, Christopher T French
• Journal: mBio (mBio) Vol. 12 Issue 1 (01 19 2021) ISSN: 2150-7511 [Electronic] United States
• PMID: 33468703 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Stone et al.

Chemical References

• Antimetabolites
• Antiviral Agents
• Azo Compounds
• Isoquinolines
• Poly(ADP-ribose) Polymerase Inhibitors
• Quinazolinones
• remdesivir
• Adenosine Monophosphate
• stenoparib
• Poly(ADP-ribose) Polymerases
• Alanine

Topics

• Adenosine Monophosphate (analogs & derivatives, pharmacology)
• Alanine (analogs & derivatives, pharmacology)
• Animals
• Antimetabolites (pharmacology)
• Antiviral Agents (pharmacology)
• Azo Compounds
• COVID-19 (virology)
• Chlorocebus aethiops
• Coronavirus NL63, Human (drug effects, enzymology)
• Drug Repositioning
• Humans
• Isoquinolines (pharmacology)
• Poly(ADP-ribose) Polymerase Inhibitors (pharmacology)
• Poly(ADP-ribose) Polymerases (metabolism)
• Quinazolinones (pharmacology)
• SARS-CoV-2 (drug effects, enzymology)
• Vero Cells
• Virus Replication (drug effects)
• COVID-19 Drug Treatment