4.2 Potential COVID-19 therapies
Considering ACE-2 the only viral receptors, a new study has been proposed that Lactoferrin, an orally nutritional supplement, may be potentially useful against COVID-19. In addition to its unique immunomodulatory and anti-inflammatory effects, Lactoferrin has been stated to possibly occupy ACE-2 receptors preventing SARS-CoV-2 from attaching to the host cells (Kell et al., 2020), however it is not ensured clinically till now.
Most of repurposed drugs used for treating COVID-19 are directed mainly towards blocking the induced cytokine storm, however this COVID-19-related sepsis argues now for investigating a different therapeutic approach (Remy et al., 2020).
Since, the morbidity/mortality rate in septic patients was reported to be correlated with the plasma level of ET-1, reducing its level will minimize all unwanted reactions mediated by ET-1 receptors. The observation that may explain why anti-inflammatory drugs like anti- TNF-α and IL-1-based therapies have been failed in treating sepsis, opposite to clinical trials that suggested the application of ET-1 receptor blockers as an effective strategy (Kowalczyk et al., 2015). In addition, decreasing ET-1 level may interrupt the fibrotic pathway regulated by TGF- β1; inhibiting the induction of pulmonary fibrosis.
Because ET-1 was previously reported to be one of the substrates that could be potentially degraded by endogenous NEP (neutral endopeptidase) (Abassi et al., 1992), that pushed us to predict that enhancing NEP activity may become a prerequisite to defeat COVID-19 ghost (El Tabaa and El Tabaa, 2020).
NEP is a type II integral transmembrane metallopeptidase, which was clearly detected in various tissues like lung, kidney, brain, intestine, and vascular endothelium (Li et al., 1995) as well as in many inflammatory cells including neutrophils (Connelly et al., 1985). In the airways, NEP has been found to be expressed in the epithelium (Sont et al., 1997), smooth muscle cells (Di Maria et al., 1998), and fibroblasts (Kletsas et al., 1998).
NEP also has a high cleaving affinity towards some potent inflammatory and vasoactive peptides other than ET-1 including bradykinins (BKs), N-formyl-L-methionyl- L-leucyl-L-phenylalanine (fMLP) and atrial natriuretic peptide (ANP); that emphasize on its role in alleviating the airway inflammatory processes (Connelly et al., 1985; Shimamoto et al., 1994).
Several studies ensured that destroying or down regulating NEP may lead to further pathophysiological changes. This involves an increase in vascular permeability, recruitment and activation of inflammatory cells, particularly neutrophils. Neutrophils chemotaxis will lead to the release of neutrophil elastase enzymes (e.g., Cathepsin G), which may exert further destructive effects on airway tissues, leading to worsening and progression of the disease (Borson, 1991).
Therefore, reducing NEP activity either by cigarette smoking (Dusser et al., 1989), hypoxia (Carpenter and Stenmark, 2001) or respiratory pathogens like parainfluenza virus type 1, rat corona-virus, and Mycoplasma pulmonis (Jacoby et al., 1988; Borson et al., 1989), will be a clear explanation for their associated inflammatory cascades. Considering multiple activities of NEP in regulating local inflammatory neuropeptides within alveolar microenvironment and nearby vascular cells (Wick et al., 2011), it may exhibit a good target for counteracting the airway inflammation, coagulopathy and pulmonary fibrosis associated with COVID-19 infection.
Referring to the studies searching for agents that may up-regulate NEP gene expression; enhancing its activity and promoting its action (Borson, 1991), a variety of selective enhancers are pre-clinically developed involving drugs (glucocorticoids) (Borson and Gruenert, 1991), hormones (androgens (Yao et al., 2008) and estrogen (Xiao et al., 2009)) or natural products (Apigenin, Luteolin, and Curcumin, (-)-Epigallocatechin-3-gallate and Resveratrol) (Ayoub and Melzig, 2008; Chang et al., 2015; El-Sayed and Bayan, 2015).
Along with, Rolipram, an investigative PDE4i, has also been examined; suggesting that increasing the levels of intracellular cAMP was directly correlated with enhanced NEP activity, which in turn may prolong and potentiate the cAMP-mediated short-term anti-inflammatory mechanism (Graf et al., 1995; Ayoub and Melzig, 2008).
That outcome may declare that roflumilast, a highly selective PDE4i, can exert its efficient anti-inflammatory effect via enhancing cAMP level as well as NEP activity. Accordingly, we predict that roflumilast may be one of the most useful drugs that is expected to play a great role in treating COVID-19. However, until this moment, no study declares the potential fundamental pathways contributing to relying roflumilast on NEP activity.
5. Roflumilast overview
Roflumilast is recorded to be a highly selective long-acting inhibitor of PDE4 isoenzyme, to which its use will be surely accompanied with an increase in the level of intracellular cAMP (Rabe, 2011).