Neutrophil Extracellular Traps (NETs) and Damage-Associated Molecular Patterns (DAMPs): Two Potential Targets for COVID-19 Treatment

Table 1

immunomodulatory drugs in clinical development to treat SARS-CoV-2. This table lists agents under investigation and/or theoretically being considered for patient management. At this time, no recommendation can be made for any of these agents and some of them are off-label use.

Drug or cocktail	Status and mechanisms	NETs	DAMPs	Autophagy	Clinical trials (trial posting date)
Adalimumab	Anti-TNF-α humanized mAb able to suppress the physiologic response to TNF-α, which is part of the inflammatory response in autoimmune and immune-mediated disorders	No data	No data	In autoimmune disease, it inhibits autophagy, enhancing regulation	One clinical trial enrolled in China (ChiCTR2000030089) in combination with standard treatment in severe disease
Anakinra	IL-1 receptor antagonist hypothesized to quell cytokine storming. No data available as adjunctive therapy for SARS-CoV-2	Possible role in blocking NET formation	Anti-IL1R may have a role in blocking DAMP release	Anti-IL1R may have a role in restoring a regulatory function	12 clinical trials as single drug or in combination are enrolling patients in Europe
Bevacizumab	Recombinant humanized mAb that prevents vascular endothelial growth factor (VEGF) association with endothelial receptors Flt-1 and KDR approved for multiple cancers in the US	No data	No activity	Autophagy promotes resistance to Bevacizumab	Being evaluated in two clinical trials in China for COVID-19 (NCT04305106 and NCT04275414) and one international trial (NCT04344782), no data are currently available to support its use
Chloroquine or hydroxychloroquine	Endosomal acidification fusion inhibitor	Inhibition of NETosis as a consequence of autophagy blockade	Inhibition of HMGB1 activity in a septic in vivo model	Blocks autophagosome fusion and degradation	At least 300 trials, alone and in combination, for mild symptoms and prophylaxis, have been registered with the FDA and Chinese clinical trials
Convalescent plasma	Plasma from convalescent patients who have recovered from the SARS-CoV-2 infection has been used with success much in the same way as for SARS-CoV-1, MERS, Ebola, and H1N1 influenza	Possible role overlapping IVIg	Possible role overlapping IVIg	Possible role overlapping IVIg	Up to 250 clinical trials enrolled patients with severe SARS-CoV-2 disease in the US, China, Italy, and Mexico registered with the FDA and Chinese clinical trials
Diflunisal	Diflunisal, a nonsteroid anti-inflammatory drug (NSAID) included in the salicylate class, has a specific indication to prevent flogosis and pain control in joint disease	No data	Blocks immune cell recruitment inhibiting HMGB1/CXCL12 activation	No data	No clinical trial for SARS-CoV-2
Disulfiram	Thiuram derivative that blocks alcohol oxidation, demonstrating ability to competitively inhibit the papain-like proteases of SARS but no clinical data. No in vitro or clinical data available for SARS-CoV-2	No data	Reduces the release of DAMPs in apoptotic cells	Dual role in Disulfiram mechanism studied in cancer	None
Eculizumab	Humanized IgG mAb that binds to complement protein C5 and prevents formation of membrane attack complex (MAC)	Blocking NET formation via complement activation	No data	No data	Being evaluated in a clinical trial (NCT04288713) for SARS-CoV-2 to quell immune response. New clinical trial (NCT04346797) is recruited as a single agent
Heparin/low molecular weight heparin	Heparin binds to the enzyme inhibitor antithrombin III (AT), causing a conformational change that results in activation and consequent inactivation of thrombin, factor Xa, and other proteases. Possible role in immune modulation	Reduction of NETosis due to a reduction of autophagy	Inhibition of activity via blockade of HMGB1 binding to immune cell surface	Reduction of neutrophil activation autophagy	At least 40 clinical trials planned to evaluate its efficacy in the prevention of SARS-CoV-2 complications
Hyperbaric oxygen	Hyperbaric oxygen therapy is a medical use of oxygen at an ambient pressure higher than atmospheric pressure. It reduces inflammation, modulating cytokine release, and increases ROS production, reduces apoptosis, and modulates leukocyte activation and adhesion	Reduction of ROS-dependentNET release	Reduced activation of HMGB1 pathways	Inhibits autophagy activation reducing ROS	8 clinical trials are ongoing to evaluate its efficacy in ARDS and pneumonia
Interferon alpha-2b alone or in combination with other drugs	Interferon α-2b is a recombinant cytokine with antiviral properties; ribavirin is a guanine derivative; as above	Type I IFN enhance NETosis	HMGB1 is related to IFNα in sustaining inflammation	Possible role in enhancing antiviral autophagy	60 clinical trials registered as a single agent or in combination for SARS-CoV-2
Intravenous immunoglobulin (IVIg)	IVIg remain on critical national shortage in the US. The benefit in patients with SARS-CoV-2 is unclear	IVIg reduce NET formation	Protection against HMGB1-induced cell death modulating TLR and RAGE expressions	IVIg may have a role in modulating a regulatory function	More than 250 clinical trials are planned all over the world to evaluate efficacy in SARS-CoV-2 pneumonia
Methylprednisolone	Synthetic corticosteroid that binds to nuclear receptors to dampen proinflammatory cytokines	Reduction of NET formation in in vitro and in vivo model	Reduces the release of HMGB1 and its interaction with TLR4	Modulation of regulatory autophagy	25 clinical trials in COVID-19 disease as a single agent or in combination with standard care or mAb in US and China
Remdesivir	Adenosine analogue that leads to premature or delayed termination of the viral RNA chains	No data	No data	No data	First approved specifically to treat COVID-19
Sarilumab	IL-6 receptor antagonist FDA-approved for rheumatoid arthritis	Possible role in blocking NET formation	No data	Role in blocking regulatory autophagy	15 clinical trials in SARS-CoV-2 disease as a single agent or in combination
Sirolimus	Commercial drug form of rapamycin blocks mTOR and subsequent pathways, reducing cytokine (such as IL-6 and TNF-α) expression	Enhances NETosis also without external stimuli	Reduces the expression of HMGB1	Stimulation of autophagy as a direct effect of mTOR blockade	4 clinical trials as a single agent, enrolling patients affected by SARS-CoV-2 disease
Tocilizumab	Humanized mAb targeting IL-6	Possible role in blocking NET formation	No data	Role in blocking hypoxia-induced autophagy	Up to 60 clinical trials in different countries

Last search run on June 06 using https://clinicaltrials.gov and http://www.chictr.org.cn. This table lists agents being investigated and/or theoretically considered for the management of SARS-CoV-2-infected patients. At this time, no recommendation can be made for any of these agents. In general, they should be avoided without additional supporting evidence.