Ac2-26 mimetic peptide of annexin A1 to treat severe COVID-19: A hypothesis.

The Coronavirus Diseases-2019 (COVID-19) pandemic leads many researchers around the world to study the SARS-CoV-s2 infection and pathology to find a treatment for it. This generates a massive production of papers including pre-clinical, clinical and revisions but till now no specific treatment were identified. Meanwhile, like other coronavirus infections, COVID-19 leads to the cytokine storm syndrome resulting in hyperinflammation, exacerbated immune response and multiple organ dysfunctions indicating that drugs that modulate this response, as glucocorticoids could be a treatment option. However glucocorticoids have several side effects or usage limitations. In this sense a drug with anti-inflammatory effects and capable to reduce inflammation but with less after-effects could be a powerful tool to combat COVID-19. Thus the Ac2-26 Mimetic Peptide of Annexin A1 emerges as a possible therapy. The peptide has many anti-inflammatory effects described including the reduction of interleukin (IL)-6, one of the main mediators of cytokine storm syndrome. Therefore the hypothesis to use the Ac2-26 peptide to treat severe COVID-19 will be highlighted in this paper.

Introduction

The COVID-19 caused more than 1 million deaths worldwide being a important heath problem [1]. This drove many research groups to better understand the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) biology and pathology to offer new insights for treatments and development of new therapies. Besides a lot of the patients have a good prognosis there are still some individuals that evolve to severe disease and even death [2]. Death seems to be related with the acute respiratory distress syndrome (ARDS) and multiple-organ failure (MOF) as a consequence of the cytokine storm syndrome (CSS) which was detected in several critical patients with COVID-19 [3], [4]. Zhou and colleagues showed that IL-6 and inflammation are increased in critical patients with COVID-19 [5]. The higher levels of IL-6 seems fundamental to the disease aggravation and development of ARDS and MOF [6]. Hence, drugs that can control inflammation and IL-6 secretion could be a relevant tool to reduce COVID-19 severity and associated deaths [7], [8]. It was observed that treatment for 10 days with the steroid anti-inflammatory dexamethasone was able to reduce death in patients with severe condition [8]. However it is well know that glucocorticoids have many side effects [9] including the immunosuppressive action that could potentially lead to increase of plasma viral load. It is well described that many anti-inflammatory effects of glucocorticoids are mediated by Annexin-A1 (ANXA1) protein witch act by activation of formyl peptide receptors (FPR) family [10]. The anti-inflammatory effects of ANXA1 can be mimic by it N-terminal domain with 26 amino acid termed Ac2-26 peptide [11]. Herein is presented the many effects of Ac2-26 peptide that support the use of it to treat severe COVID-19.

The hypothesis

During the acute inflammatory response several pro-inflammatory mediators are produced as well the endogenous anti-inflammatory and pro-resolving mediators [12], [13]. These anti-inflammatory mediators act regulating the inflammation by reducing cell migration, edema, cytokine production as well promoting inflammatory cells apoptosis [14]. One of the anti-inflammatory mediators is a protein regulated by glucocorticoid named annexin-A1 (ANXA1), previously lipocortin-1 [15], [16]. ANXA1 is a member a family of proteins that binds to membrane phospholipids resulting in inhibition of phospholipase A2 and eicosanoids production [11]. In many studies the anti-inflammatory effects of ANXA1 was reproduced by it N-terminal region of 26 amino acids termed Ac2-26 [10], [17]. This peptide exerts it effects by activation of the formyl peptide receptor type 1 (FPR1) and type 2 (FPR2) [18], [19]. The anti-inflammatory effects of Ac2-26 were observed in many experimental models where inflammation is an important component including allergic conjuntivits [20], skin allograft survival [21], brain sepsis [22], experimental pneumococcal pneumonia [23], lung injury after ischemia–reperfusion [24], chronic obstructive pulmonary disease [25], allergic asthma and inflammation [26], [27] and pain [28]. Table 1 summarizes the anti-inflammatory effects described for the Ac2-26 peptide.

Table 1

Summary of the anti-inflammatory effects of Ac2-26 peptide.

Inflammatory component	Main result observed	References
Neutrophil	Inhibition of neutrophil migration and adhesion, increased L-selectin shedding, reduction of myeloperoxidase activity and induction of apoptosis	[17], [20], [25], [27], [29], [30], [31], [32], [33], [34], [35]
IL-6	Reduce production and signaling	[30], [32], [36], [37]
IL-1β	Reduce production and effects on neutrophil migration	[28], [32], [36], [38], [39]
IL-8	Reduce production	[29], [31]
Interferon-γ	Reduce production	[36], [40]
TNF-α	Reduce production and intracellular activated pathways	[28], [29], [30], [36], [41], [42]
MCP-1 and MIP-1α	Reduce production	[28], [42]
Mast cell activation	Reduce cell degranulation and release of histamine	[27]
Edema	Reduce exudate	[27], [29]
Pain	Reduce pain response	[28], [38]
NFkB	Reduce NFkB activation/translocation	[29], [31]
ROS	Blocks NADPH oxidase activity induced by TNF-α	[41]

In this moment evidence suggests that host immune response contributes to the severity of COVID-19 as well the higher admissions at intensive care unit (ICU) and mortality [43], [44], [45]. In the severe cases of infected patients it was observed an increased plasma concentration of many pro-inflammatory cytokines as TNF-α IL-6, IL-8, G-CSF, MCP-1, IP-10, MIP-1α characterizing the CSS and the consequent hyperinflammation and MOF [45]. Recent works suggested that drugs as glucocorticoid, anti-IL-6 antibody (Tocilizumab), IL-1β antagonist (Anakinra) could modulate this extreme host reaction resulting in a better prognostic for severe COVID-19 patients [46]. Recently the RECOVERY trial from the Oxford University showed that treatment with 6 mg of dexamethasone for 10 days reduce the mortality of patients with the severe form of COVID-19 [8]. This result was highly associated the presence of lung inflammation. The use of glucocorticoids was previously suggested to others lung infections (e.g. MERS, SARS, severe influenza and community-acquired pneumonia) however the lack of randomized/controlled trials and the heterogeneity of doses or medical conditions discourage it use [47], [48], [49], [50]. Moreover glucocorticoid is not indicated in patients with comorbidities like Cushing syndrome or non-compensate diabetes mellitus [51], [52]. In this way a drug with similar anti-inflammatory profile but lacking the side effects could be a tool to treat these patients.

As mentioned above, the ANXA1 derived peptide Ac2-26 share many anti-inflammatory effects of the glucocorticoids including the inhibition of several cytokines production (see Table 1). These effects were observed in different pre-clinical models using in vitro and in vivo experiments. The potent inhibitory effect of Ac2-26 over inflammation indicates that the ANXA1-derived peptide could be relevant to reduce the COVID-19 severity and associated deaths. The increased levels of IL-6 and others mediators of inflammation like IL-1β, TNF-α triggers the so called cytokine storm syndrome which is closely related with the COVID-19 evolution and seems responsible for 28% of the deaths [3], [6]. The cytokine storm promotes an uncontrolled inflammation with directly lung failure and it inflicts multi-organ damage failure, mostly in cardiac, hepatic and renal systems. In vitro and in vivo studies demonstrated that Ac2-26 peptide was able to reduce inflammation and enrolled mediators in many models where inflammation is relevant and then it was suggested to treat several diseases as allergy, cancer, stroke, sepsis or ischemia [11], [24], [53]. In lungs, Ac2-26 showed protective effects in by reducing inflammation in different conditions [24], [25], [29], [42] suggesting it could have an important paper during COVID-19 treatment. The myocardium damage is also present in patients with severe COVID-19 [54]. In this tissue the Ac2-26 showed a protective effect after ischemia–reperfusion injury [55]. Acute kidney injury rate to 50% of patients in severe COVID-19 being a risk factor for mortality [56]. A work showed that annexin-A1 N-terminal derived-peptide can protect renal tissue against Bothrops moojeni Venom-induced inflammation in rats [32]. Complementary, Ac2-26 showed renal protection against drug-associated inflammation (e.g. tacrolimus or cyclopsporin) or in model of ischemia–reperfusion [57], [58], [59]. Taking together these findings suggest that Ac2-26 could have a relevant protective action on hyperinflammation-driven MOF during COVID-19 and probably reducing severity and death.

Other point to mention is that during COVID-16 occurs coagulopathy with increased venous coagulation [60]. Besides there are no evidence of direct action of Ac2-26 on platelet aggregation there are two papers that presented effects of ANXA1 on coagulation. The first work of Kuster and colleagues observed an anti-plaque effect of human-recombinant ANXA1 in mice with atherosclerosis [61]. The second described a novel role for ANXA1, the ability to activate anti-thrombo-inflammatory circuits in cerebral during ischemia–reperfusion [62]. Since many the effects of ANXA1 are mediated by the interaction of it N-terminal domain with the FPR family, probably the Ac2-26 mimetic peptide would have similar effects on coagulation and a bonus effect in COVID-19 treatment.

Finally there are a few works with the actions of the full length ANXA1 protein in influenza infections. Schloer et al observed that ANXA1 was able to expand the number of alveolar macrophages by activating the FPR2 receptor resulting in a protective effect against influenza A infection. This protection was associated with significantly increased survival, impaired viral replication in the respiratory tract and finally a reduction of lungs damage [63]. However in a recent paper was suggested that annexin-A1 facilitate influenza infection [64]. More studies are needed to better understand the real participation of ANXA1 and it N-terminal-derived peptide on virus infection and the importance of it during the timeline of virus-based diseases especially in coronavirus diseases.

Conclusion

Ac2-26, a mimetic peptide of the full length ANXA1 protein, has anti-inflammatory effects described in several models of inflammation and disease. So it could reduce cytokine storm syndrome particularly in severe COVID-19. The peptide would be a promising treatment for patients with severe respiratory symptoms and multiple organ. Additional pre-clinical and initial clinical research must be conducted to define the efficacy and safety of the Ac2-26 peptide for the SARS-CoV-2 infection.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.