Poly-ADP Ribosyl Polymerase 1 (PARP1) Regulates Influenza A Virus Polymerase

Westera, Liset; Jennings, Alisha M.; Maamary, Jad; Schwemmle, Martin; García‐Sastre, Adolfo; Bortz, Eric

doi:10.20944/preprints201810.0673.v1

Cited by 3 publications

(3 citation statements)

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“…Besides the known roles for the PARP1 and PARP2 enzymes in DNA repair (14,15), members of the PARP family have numerous additional functions (16). The 18 known human PARPs appear to differentially affect viral replication; some exhibit proviral activity and others exhibit antiviral roles (7,(17)(18)(19)(20)(21). In coronavirus, the N protein is mono (ADP) ribosylated (MARylated) during infection.…”

Section: Importancementioning

confidence: 99%

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

Zarn

Jaramillo

Zapata

et al. 2021

Preprint

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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 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.

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Section: Importancementioning

confidence: 99%

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

Zarn

Jaramillo

Zapata

et al. 2021

Preprint

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“…It has been reported that efficient HIV-1 (Human Immunodeficiency Virus-1) integration and transcriptional activation also require PARP1 activity (Ha et al, 2001;Yu, Liu, Yang, & Zhou, 2018). Recently, PARP1 was shown as a cofactor in the activity of the influenza A virus polymerase (Westera et al, 2019). In another study, Shou et al showed that PARP1 functions as a regulator of NF-kB by promoting its nuclear translocation and by facilitating its binding to the NF-kB response sequences in macrophages upon vaccinia virus infection; therefore PARP1 can provide viral control through natural killer (NK) cell recruitment to the site of infection (Shou, Fu, Huang, Yang, 2019)…”

Section: Viral Infectionsmentioning

confidence: 99%

PARP1 (poly(ADP-ribose) polymerase 1)

Tunçer¹,

Kavak²

2020

Atlas of Genetics and Cytogenetics in Oncology and Haematology

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PARP1 (poly(ADP-ribose) polymerase 1) is a nuclear protein involved in the regulation of various biological processes including apoptosis, DNA repair for the maintenance of genome integrity, epigenetic marking of chromatin, assembly of higher-order chromatin structures, transcriptional activation, differentiation, proliferation, and cell cycle. Particularly, due to its decisive role in several DNA repair pathways, the inhibition of PARP1 has emerged as a prominent therapeutic option in cancer treatment, by improving the efficiency of chemotherapeutics or radiation therapy.

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“…PARP1 is observed to be a facilitator of influenza A virus (IAV) infection through regulation of RNA dependent RNA polymerase (Rdrp polymerase) of influenza A virus. However, endogenous PARylation inhibited Rdrp assembly (Westera et al, 2019). Host protein PARP1 is reported to facilitate propagation of influenza A virus through degradation of interferon receptor type I (IFNAR) (Xia et al, 2020).…”

Section: Parp1 and Viral Infectionmentioning

confidence: 99%

Understanding the role of Poly(ADP-ribose) polymerase (PARP1) and PARP inhibitors in viral infection and pathogenesis

Rajawat¹,

Chandra²

2020

Preprint

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Poly (ADP-ribose) polymerase 1 (PARP1) is a post-translational modifying enzyme and is also known to act as transcription factor and co-activator. PARP1 has been shown to be involved with diseases resulting in increased inflammation and several viral diseases have also been associated with PARP1 activation. PARP1 facilitates influenza A virus entry in host cells by degrading interferon receptor type I. PARP1 regulates expression of NFkB and downstream cytokine production and its inhibition is known to attenuate the expression of inflammatory cytokines. Thus, PARP1 plays an important role in host-pathogen interactions and pathogenesis. Moreover, pre-clinical and in vitro studies have shown that PARP1 inhibition may affect viability of several viruses including affecting replication of the SARS-CoV virus, a distant relative of the SARS-CoV-2 virus, the one which caused the SARS epidemic of 2002. Covid-19 has been declared a global pandemic; with symptoms of the disease now not limited to respiratory distress alone. Severe inflammation is observed in the lungs leading to a surge of cytokine release systemically, affecting heart function, ischemia and stroke. Inflammatory cytokines which are associated with severe comorbidities and mortalities due to chronic diseases are being upregulated in an acute fashion. There is no immediate treatment, and only palliative care is being provided. The current review will discuss mechanisms of PARP1 activation during viral infection, inflammatory diseases, cytokine expression and possibility of PARP1 in regulating cytokine storm and hyper-inflammation seen with Covid-19.

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Poly-ADP Ribosyl Polymerase 1 (PARP1) Regulates Influenza A Virus Polymerase

Cited by 3 publications

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

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

PARP1 (poly(ADP-ribose) polymerase 1)

Understanding the role of Poly(ADP-ribose) polymerase (PARP1) and PARP inhibitors in viral infection and pathogenesis

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