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

mBio ◽  
2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Nathan E. Stone ◽  
Sierra A. Jaramillo ◽  
Ashley N. Jones ◽  
Adam J. Vazquez ◽  
Madison Martz ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Clinical Trials ◽  
Viral Replication ◽  
Phase Ii ◽  
Parp Inhibitor ◽  
Target Range ◽  
Phase Ii Clinical Trials ◽  
Human Coronaviruses ◽  
Respiratory Coronavirus

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.

scholarly journals Stenoparib, an inhibitor of cellular poly (ADP-ribose) polymerase (PARP), blocks replication of the SARS-CoV-2 human coronavirus in vitro

2020 ◽  
Author(s):  
Nathan E. Stone ◽  
Sierra A. Jaramillo ◽  
Ashley N. Jones ◽  
Adam J. Vazquez ◽  
Madison Martz ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Clinical Trials ◽  
Viral Replication ◽  
Parp Inhibitor ◽  
Stage Ii ◽  
Target Range ◽  
Advanced Stages ◽  
Post Entry ◽  
Respiratory Coronavirus

ABSTRACTBy 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, 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 HCoV-NL63 human seasonal respiratory coronavirus. Compared to remdesivir, which inhibits viral replication downstream of cell entry, stenoparib impedes entry and post-entry 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 standalone or as part of combinatorial therapy with remdesivir should be a valuable addition to the arsenal against COVID-19.ImportanceNew 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 Stage II clinical trials for the treatment of ovarian cancer and its safety and dosage in humans has 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 post-entry 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.

scholarly journals TheREnantiomer of the Antitubercular Drug PA-824 as a Potential Oral Treatment for Visceral Leishmaniasis

2013 ◽  
Vol 57 (10) ◽  
pp. 4699-4706 ◽  
Author(s):  
Stephen Patterson ◽  
Susan Wyllie ◽  
Laste Stojanovski ◽  
Meghan R. Perry ◽  
Frederick R. C. Simeons ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Visceral Leishmaniasis ◽  
Phase Ii ◽  
Leishmania Donovani ◽  
Oral Treatment ◽  
Parasite Burden ◽  
Content Type ◽  
Phase Ii Clinical Trials

ABSTRACTThe novel nitroimidazopyran agent (S)-PA-824 has potent antibacterial activity againstMycobacterium tuberculosisin vitroandin vivoand is currently in phase II clinical trials for tuberculosis (TB). In contrast toM. tuberculosis, where (R)-PA-824 is inactive, we report here that both enantiomers of PA-824 show potent parasiticidal activity againstLeishmania donovani, the causative agent of visceral leishmaniasis (VL). In leishmania-infected macrophages, (R)-PA-824 is 6-fold more active than (S)-PA-824. Both des-nitro analogues are inactive, underlining the importance of the nitro group in the mechanism of action. Although thein vitroandin vivopharmacological profiles of the two enantiomers are similar, (R)-PA-824 is more efficacious in the murine model of VL, with >99% suppression of parasite burden when administered orally at 100 mg kg of body weight−1, twice daily for 5 days. InM. tuberculosis, (S)-PA-824 is a prodrug that is activated by a deazaflavin-dependent nitroreductase (Ddn), an enzyme which is absent inLeishmaniaspp. Unlike the case with nifurtimox and fexinidazole, transgenic parasites overexpressing the leishmania nitroreductase are not hypersensitive to either (R)-PA-824 or (S)-PA-824, indicating that this enzyme is not the primary target of these compounds. Drug combination studiesin vitroindicate that fexinidazole and (R)-PA-824 are additive whereas (S)-PA-824 and (R)-PA-824 show mild antagonistic behavior. Thus, (R)-PA-824 is a promising candidate for late lead optimization for VL and may have potential for future use in combination therapy with fexinidazole, currently in phase II clinical trials against VL.

Naphthoquinone Derivatives Isolated from Plants: Recent Advances in Biological Activity

2020 ◽  
Vol 20 (19) ◽  
pp. 2019-2035
Author(s):  
Esmaeil Sheikh Ahmadi ◽  
Amir Tajbakhsh ◽  
Milad Iranshahy ◽  
Javad Asili ◽  
Nadine Kretschmer ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Biological Activity ◽  
Small Molecules ◽  
Anticancer Activity ◽  
Clinical Significance ◽  
Phase Ii ◽  
Biological Activities ◽  
Phase Ii Clinical Trials ◽  
Naturally Occurring ◽  
The Subject

Naturally occurring naphthoquinones (NQs) comprising highly reactive small molecules are the subject of increasing attention due to their promising biological activities such as antioxidant, antimicrobial, apoptosis-inducing activities, and especially anticancer activity. Lapachol, lapachone, and napabucasin belong to the NQs and are in phase II clinical trials for the treatment of many cancers. This review aims to provide a comprehensive and updated overview on the biological activities of several new NQs isolated from different species of plants reported from January 2013 to January 2020, their potential therapeutic applications and their clinical significance.

Counterpoint: Chemosensitivity Assays for Recurrent Ovarian Cancer

2011 ◽  
Vol 9 (1) ◽  
pp. 121-124 ◽  
Author(s):  
Maurie Markman
Keyword(s):  
Ovarian Cancer ◽  
Clinical Trials ◽  
Recurrent Ovarian Cancer ◽  
Evidence Based ◽  
Chemosensitivity Assay ◽  
Reliable Evidence ◽  
In Vitro Chemosensitivity ◽  
Frequent Use ◽  
Chemosensitivity Assays

Unfortunately, no reliable evidence-based data have shown any in vitro chemosensitivity assay strategy to be clinically useful in the management of recurrent ovarian cancer, despite frequent use. Several clinical trials have been proposed with the potential to support or refute the relevance of these approaches.

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