PAD Inhibitors as a Potential Treatment for SARS-CoV-2 Immunothrombosis

Abstract

Since the discovery of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in December 2019, the virus’s dynamicity has resulted in the evolution of various variants, including the delta variant and the more novel mu variant. With a multitude of mutant strains posing as challenges to vaccine efficacy, it is critical that researchers embrace the development of pharmacotherapeutics specific to SARS-CoV-2 pathophysiology. Neutrophil extracellular traps and their constituents, including citrullinated histones, display a linear connection with thrombotic manifestations in COVID-19 patients. Peptidylarginine deiminases (PADs) are a group of enzymes involved in the modification of histone arginine residues by citrullination, allowing for the formation of NETs. PAD inhibitors, specifically PAD-4 inhibitors, offer extensive pharmacotherapeutic potential across a broad range of inflammatory diseases such as COVID-19, through mediating NETs formation. Although numerous PAD-4 inhibitors exist, current literature has not explored the depth of utilizing these inhibitors clinically to treat thrombotic complications in COVID-19 patients. This review article offers the clinical significance of PAD-4 inhibitors in reducing thrombotic complications across various inflammatory disorders like COVID-19 and suggests that these inhibitors may be valuable in treating the origin of SARS-CoV-2 immunothrombosis.

NETosis and Neutrophil Extracellular Traps in COVID-19: Immunothrombosis and Beyond

“…These antiproteases have undergone preclinical ( 136 ) or clinical testing ( 11 , 60 ) to demonstrate their efficacy in COVID-19. PAD4 is another crucial pro-NET enzyme that is upregulated in COVID-19 and is responsible for NET release ( 138 , 145 ). Therefore, the use of PAD4 inhibitors, such as Cl-amidine, YW-56, and GSK484, may prevent both the prothrombotic and proinflammatory effects of SARS-CoV-2 by reducing NET production ( 138 ).…”

“…PAD4 is another crucial pro-NET enzyme that is upregulated in COVID-19 and is responsible for NET release ( 138 , 145 ). Therefore, the use of PAD4 inhibitors, such as Cl-amidine, YW-56, and GSK484, may prevent both the prothrombotic and proinflammatory effects of SARS-CoV-2 by reducing NET production ( 138 ). For example, Cl-amidine has been shown to suppress NET release in both SARS-CoV-2-infected healthy neutrophils and blood neutrophils from COVID-19 patients ( 13 ).…”

“…For example, Cl-amidine has been shown to suppress NET release in both SARS-CoV-2-infected healthy neutrophils and blood neutrophils from COVID-19 patients ( 13 ). Cl-amidine also prevents apoptosis of lung epithelial cells due to NET release, suggesting that PAD4 inhibitors could be used to prevent immunothrombosis and lung injury in COVID-19 ( 13 , 138 ). The third strategy involves mediating NET degradation.…”

SARS-Cov2 acute and post-active infection in the context of autoimmune and chronic inflammatory diseases

“…RA development occurs in genetically predisposed individuals exposed to environmental factors, which ultimately result in an inflammatory destructive synovial response [ 128 ]. As reported with tobacco smoking and air pollutants, COVID-19 can act on cells in mucosal sites (mouth, lung and gut) to promote the induction of PADI-4 and in turn to the formation of citrullinated histones [ 129 , 130 ]. This process is suspected of becoming chronic in PACS since lung sensory neurons and the gut represent mucosal reservoirs for SARS-Cov2 [ 26 , 131 , 132 ].…”

Do Circulating Histones Represent the Missing Link among COVID-19 Infection and Multiorgan Injuries, Microvascular Coagulopathy and Systemic Hyperinflammation?

“…This landscape encourages the search for other pharmacological agents [ 38 , 48 ], also with endothelial-protective and histone-neutralizing properties in COVID-19 patients (e.g., apolipoprotein A–I, activated protein C, thrombomodulin, recombinant anti-histone IgG, peptidylarginine deiminases inhibitors, etc.) [ 51 , 52 , 53 , 54 ], but also to develop a circulating histone sensitive assay for laboratory medicine for better stratifying the risk of COVID-19 patients (as well as for sepsis-affected patients) [ 2 , 23 ].…”