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).