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