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

Katherine E Zarn; Sierra A Jaramillo; Anthony R Zapata; Nathan E Stone; Ashley N Jones; Haley E Nunnally; Erik W Settles; Ken Ng; Paul S Keim; Steen Knudsen; Patricia M Nuijten; Aloys S L Tijsma; Christopher T French

doi:10.1371/journal.pone.0272916

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

PLoS One. 2022 Sep 14;17(9):e0272916. doi: 10.1371/journal.pone.0272916. eCollection 2022.

Authors

Katherine E Zarn¹, Sierra A Jaramillo¹, Anthony R Zapata¹, Nathan E Stone¹, Ashley N Jones¹, Haley E Nunnally¹, Erik W Settles^{1

2}, Ken Ng¹, Paul S Keim^{1

2}, Steen Knudsen³, Patricia M Nuijten⁴, Aloys S L Tijsma⁴, Christopher T French^{1

2

5}

Affiliations

¹ Pathogen and Microbiome Institute, Northern Arizona University, Flagstaff, Arizona, United States of America.
² Department of Biological Sciences, Northern Arizona University, Flagstaff, Arizona, United States of America.
³ Allarity Therapeutics Europe, Hørsholm, Denmark.
⁴ Viroclinics-DDL, Rotterdam, The Netherlands.
⁵ COVID-19 Testing Service Center, Pathogen and Microbiome Institute, Northern Arizona University, Flagstaff, Arizona, United States of America.

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. Here we show that stenoparib effectively inhibits a SARS-CoV-2 wild type (BavPat1/2020) strain and four additional variant strains; alpha (B.1.1.7), beta (B.1.351), delta (B.1.617.2) and gamma (P.1) in vitro, with 50% effective concentration (EC50) estimates of 4.1 μM, 8.5 μM, 24.1 μM, 8.2 μM and 13.6 μM, respectively. A separate experiment focusing on a combination of 10 μM stenoparib and 0.5 μM remdesivir, an antiviral drug, resulted in over 80% inhibition of the alpha variant, which is substantially greater than the effect achieved with either drug alone, suggesting at least additive effects from combining the different mechanisms of activity of stenoparib and remdesivir.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenosine Diphosphate
COVID-19 Drug Treatment*
Humans
Poly(ADP-ribose) Polymerases* / metabolism
Ribose
SARS-CoV-2

Substances

Adenosine Diphosphate
Ribose
Poly(ADP-ribose) Polymerases

Supplementary concepts

SARS-CoV-2 variants

Grants and funding

This research was supported by a grant from The Flinn Foundation awarded to PSK (grant # 2304; https://flinn.org/), the Cowden Endowment for Microbiology (a private endowment through the Northern Arizona University Foundation), and an Arizona Board of Regents Technology and Research Initiative Fund award to PSK and CTF (https://www.azleg.gov/ars/15/01648.htm). Core experiments were supported by service fees paid by Allarity Therapeutics. SK received funding in the form of salary from the commercial organization Allarity Therapeutics. PMN and ASLT received funding in the form of salary from the commercial organization Viroclinics-DDL. The funders had no additional role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.