Potential Therapeutic Roles for Direct Factor Xa Inhibitors in Coronavirus Infections

Abstract

Human factor Xa (FXa) is a serine protease of the common coagulation pathway. FXa is known to activate prothrombin to thrombin, which eventually leads to the formation of cross-linked blood clots. While this process is important in maintaining hemostasis, excessive thrombin generation results in a host of thrombotic conditions. FXa has also been linked to inflammation via protease-activated receptors. Together, coagulopathy and inflammation have been implicated in the pathogenesis of viral infections, including the current coronavirus pandemic. Direct FXa inhibitors have been shown to possess anti-inflammatory and antiviral effects, in addition to their established anticoagulant activity. This review summarizes the pharmacological activities of direct FXa inhibitors, their pharmacokinetics, potential drug-drug interactions and adverse effects, and the details of clinical trials involving direct FXa inhibitors in coronavirus disease 2019 (COVID-19) patients. Key Points Factor Xa is a serine protease in the common coagulation pathway, the excessive stimulation of which leads to a host of thrombotic conditions. Factor Xa has also been linked to inflammation as well as viral infections. In addition to their established anticoagulant properties, factor Xa inhibitors have exhibited significant anti-inflammatory and antiviral effects in several testing settings. Currently, there are > 10 clinical trials for evaluating the potential of factor Xa inhibitors in coronavirus disease 2019 (COVID-19) patients. Strategies to administer these drugs parenterally may facilitate their use in critically ill COVID-19 patients.

Biologically guided isolation and ADMET profile of new factor Xa inhibitors fromGlycyrrhiza glabraroots usingin vitroandin silicoapproaches

“…Patients with preexisting conditions, including pulmonary disease, cardiovascular disease and diabetes are at high risk of developing severe COVID-19 symptoms due to the higher baseline expression of FX in addition to other coagulation and inammatory mediators. 13,68 Based on these observations, inhibitors of FXa may have a potential role in the prophylaxis and treatment of COVID-19. This was explained by their ability to reduce cell infectivity, as well as reducing systemic inammation and coagulation.…”

“…Ten known avonoids (Fig. 1) were isolated and identied by comparing their 1 H, 13 C NMR spectra to those previously reported in literature (Tables S3, S4 and Fig. S2-S31; ESI †).…”

“…8,11,12 Direct FXa inhibitors have evolved as important part of therapeutic protocols involved in many clinical trials in (COVID-19) patients. 13 Computational approaches and virtual screening techniques are progressing towards nding candidate compounds for treatment of COVID-19 disease. 14,15 Recent studies showed the efficacy of natural bioavonoid and steroidal hormones as inhibitors of SARS-CoV-2 replication using high-throughput virtual screening.…”

Therapeutic Effectiveness and Safety of Repurposing Drugs for the Treatment of COVID-19: Position Standing in 2021

“…It is also reported that those FXa inhibitors can potentially block the viral entry of SARS-CoV-2 into the host by ceasing the fragmentation of spike protein into the S1 and S2 subunits. Thus, the concentration dependent inhibitors can obstruct the SARS-CoV-2 plaque formation in Vero E6 cells and thwart the entry of corona virus ( Al-Horani, 2020 ). Additionally, a few recent studies have suggested that FXa inhibitors can potentially inhibit TMPRSS2 and act against a wide spectrum of RNA and DNA viruses by ceasing the viral entry phase ( Du et al, 2007 ; Kim et al, 2020 ).…”

“…Additionally, a few recent studies have suggested that FXa inhibitors can potentially inhibit TMPRSS2 and act against a wide spectrum of RNA and DNA viruses by ceasing the viral entry phase ( Du et al, 2007 ; Kim et al, 2020 ). Therefore, FXa inhibitors can be a potential agent against COVID-19 attack ( Al-Horani, 2020 ). The anti-COVID-19 action of rivaroxaban is displayed in Figure 4 .…”