Immune-Modulating Drug MP1032 with SARS-CoV-2 Antiviral Activity In Vitro: A potential Multi-Target Approach for Prevention and Early Intervention Treatment of COVID-19.

Abstract

At least since March 2020, the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) pandemic and the multi-organ coronavirus disease 2019 (COVID-19) are keeping a firm grip on the world. Although most cases are mild, older patients and those with co-morbidities are at increased risk of developing a cytokine storm, characterized by a systemic inflammatory response leading to acute respiratory distress syndrome and organ failure. The present paper focuses on the small molecule MP1032, describes its mode of action, and gives rationale why it is a promising option for the prevention/treatment of the SARS-CoV-2-induced cytokine storm. MP1032 is a phase-pure anhydrous polymorph of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt that exhibits good stability and bioavailability. The physiological action of MP1032 is based on a multi-target mechanism including localized, self-limiting reactive oxygen species (ROS) scavenging activities that were demonstrated in a model of lipopolysaccharide (LPS)-induced joint inflammation. Furthermore, its immune-regulatory and PARP-1-modulating properties, coupled with antiviral effects against SARS-CoV-2, have been demonstrated in various cell models. Preclinical efficacy was elucidated in LPS-induced endotoxemia, a model with heightened innate immune responses that shares many similarities to COVID-19. So far, during oral clinical development with three-month daily administrations, no serious adverse drug reactions occurred, highlighting the outstanding safety profile of MP1032.

• Authors: Sara Schumann, Astrid Kaiser, Ferdinando Nicoletti, Katia Mangano, Paolo Fagone, Eduard van Wijk, Yu Yan, Petra Schulz, Beate Ludescher, Michael Niedermaier, Joerg von Wegerer, Pia Rauch, Christian Setz, Ulrich Schubert, Wolfgang Brysch
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 21 Issue 22 (Nov 20 2020) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 33233817 (Publication Type: Journal Article)

Chemical References

• Antiviral Agents
• Cytokines
• Immunologic Factors
• Reactive Oxygen Species
• 2,3-dihydro-1,4-phthalazinedione
• Luminol
• Poly (ADP-Ribose) Polymerase-1

Topics

• Amination
• Animals
• Antiviral Agents (chemistry, pharmacology)
• Betacoronavirus (drug effects, immunology)
• COVID-19
• Chlorocebus aethiops
• Coronavirus Infections (drug therapy, immunology)
• Cytokines (immunology)
• Female
• Humans
• Immunologic Factors (chemistry, pharmacology)
• Inflammation (drug therapy, immunology)
• Luminol (analogs & derivatives, chemistry, pharmacology)
• Male
• Mice
• Mice, Inbred C57BL
• Pandemics
• Pneumonia, Viral (drug therapy, immunology)
• Poly (ADP-Ribose) Polymerase-1 (antagonists & inhibitors, immunology)
• Reactive Oxygen Species (immunology)
• SARS-CoV-2
• Vero Cells