9. Roflumilast and COVID-19 infection
The rationale for selecting PDE4i for COVID-19 may be based on the previous findings demonstrating that inhibiting the activity of PDE4 will suppress a myriad of pro-inflammatory responses (Press and Banner, 2009). Inhibiting PDE4 will specifically prevent cAMP degradation, which in turn will decrease airway inflammation via preventing the activation and recruitment of inflammatory cells, specifically neutrophils as well as cytokines production (Barnette, 1999). The observation that drives scientists to attractively target PDE4 for treating COVID-19.
In addition to its anti-inflammatory, anti-coagulant ant anti-diabetic roles, roflumilast could be used safely in a combination with corticosteroids, recommended to be used effectively against COVID-19 infection, by improving their compromised anti-inflammatory properties and their resistance effect (Milara et al., 2015b; Wang et al., 2016).
At the same time, azithromycin, a macrolide antibiotic suggested for COVID-19 treatment, was documented to exhibit a lower affinity for cytochrome P-450A (CYP) 3A4 CYP 3A4. Thus, azithromycin would poorly interact with roflumilast because this cytochrome member resembles the main metabolic pathway for roflumilast (Westphal, 2000).
A little while ago, roflumilast is predicted to exert anti-viral effect similar to that of lopinavir/ritonavir via binding very close to the middle pocket of SARS-CoV-2 3CLpro and thereby, interfering with its activity (Hu et al., 2020). Then, roflumilast can deprive the virus from hydrolyzing the polyprotein into functional proteins required for its replication, Figure 3 (He et al., 2020). However, the preventive and therapeutic effectiveness of roflumilast against COVID-19 and its pharmacological mechanisms have not been yet extensively studied.
10. NEP-based strategy for treating COVID-19 by