Table 1.

Overview of (repurposed) drugs for COVID‐19, based on the described pathophysiological and immunopathological mechanisms.

Drug class	Drug names	Proposed mode of action	Clinical effectiveness	References
Antivirals	Remdesivir	Inhibition of RdRp	Reduces recovery time; halts progression to severe disease; no effect on survival	[209, 210]
	Lopinavir/ritonavir	Inhibition of 3CLpro	Probably ineffective	[211]
	Ivermectin	Inhibition of the IMP α/β receptor responsible for viral protein transmission into host cell nucleus Inhibition of LPS‐induced inflammation	Inconclusive	[212, 213, 214, 215, 216, 217, 218, 219]
	Ribavirin	Inhibition of viral RNA synthesis/mRNA capping	Unrealistic dosing requirement	[220]
	Favipiravir	Inhibition of RdRp	Unrealistic dosing requirement	[221, 222, 223]
	Umifenovir	Impeding trimerization of SARS‐CoV‐2 S‐protein	Probably ineffective	[224]
	Zinc	Inhibition of RdRp	Uncertain	[225]
Anticoagulants	LMWH (e.g. nadroparin)	Potentiation of antithrombin‐mediated inhibition of coagulation factors Xa and IIa Conformational change of spike S1 receptor binding domain, possibly impeding binding to ACE2	Established	[226]
	Unfractionated heparin	Reducing viral entry by interacting with S‐protein Heparanase inhibition (associated with COVID‐19 severity) Neutralisation of chemokines and cytokines, and extracellular histones Interference of leukocyte trafficking through interaction with leukocyte surface ligands, preventing leukocyte attachment and extravasation Potentiation of antithrombin‐mediated inhibition of coagulation factors Xa and IIa		[227, 228]
Immunomodulators – corticosteroids	Dexamethasone	Glucocorticoid‐mediated effects; inhibition of pro‐inflammatory signals and activation of anti‐inflammatory signals; mechanisms include lipocortin‐mediated PLA2 suppression (decreased arachidonic acid as precursor of prostaglandins, leukotrienes, and thromboxanes), COX inhibition (decreased prostaglandin synthesis), and inhibition of NF‐κB signalling, among others	Established	[229, 230, 231, 232]
	Methylprednisolone	Similar to dexamethasone	Uncertain	[232, 233, 234]
	Hydrocortisone	Similar to dexamethasone	Uncertain	[235]
Immunomodulators – biologicals	IFN β‐1a	Supplementation of interferon for antiviral defence	Uncertain ACTT‐3 trial ongoing	[236, 237]
	IL‐6R‐antagonists (e.g. tocilizumab)	Inhibition of the pro‐inflammatory action of IL‐6	Improves outcome in critical COVID‐19	[238]
	IL‐1R antagonists (e.g. anakinra)	Inhibition of the pro‐inflammatory action of IL‐1	Uncertain in severe disease; no improved outcomes in mild‐to‐moderate COVID‐19	[239, 240]
	TNF‐α inhibitors (e.g. adalimumab)	Inhibition of the pro‐inflammatory cytokine TNF‐α	Uncertain	[241, 242, 243]
	BTK inhibitors (e.g. ibrutinib)	Inhibition of the TLR signalling pathway and thereby decreased cytokine production	Uncertain	[244]
	JAK inhibitors (e.g. baricitinib, fedratinib)	Inhibition of Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway, a signalling cascade mediating cellular responses to multiple cytokines, growth factors, and other ligands (such as Ang II) after binding to their respective receptors Inhibition of upstream regulators of ACE2‐mediated endocytosis of SARS‐CoV‐2, including AAK1 and GAK	Possible	[245, 246, 247]
	Calcineurin inhibitors (e.g. cyclosporine, tacrolimus)	Inhibition of IL‐2 production and IL2‐R expression, leading to decreased T‐lymphocyte activation Potential antiviral activity by inhibiting viral replication, based on previous preclinical evidence for other coronaviruses (including SARS‐CoV)	Uncertain	[248, 249, 250, 251, 252, 253]
Complement inhibitors	Eculizumab	Terminal complement inhibitor that binds to C5 complement protein and blocks the generation of pro‐inflammatory C5a and the membrane attack complex (C5b‐9)	Uncertain	[32, 254, 255] Clinicaltrials.gov NCT04355494
Kinin–kallikrein pathway inhibitors	Lanadelumab	Inhibition of plasma kallikrein	Uncertain	Clinicaltrials.gov NCT04422509
	Icatibant	Selective antagonist of bradykinin receptor type 2	Uncertain	[256]
Angiotensin inhibitors	Angiotensin receptor blockers	Prevention of Ang II binding to AT1R, thereby counteracting vasoconstriction, proliferation, fibrosis, thrombosis, and inflammation Prevention of ACE2 downregulation by endocytosis	Uncertain	[108, 257, 258]
	ACE inhibitors	Prevention of Ang II formation	Uncertain	[108, 257, 258]
	Recombinant human ACE2 (rhACE2)	Binding of the viral spike protein and thereby neutralisation of SARS‐CoV‐2 Minimising COVID‐19‐associated organ damage as a result of RAAS hyperactivation/increased Ang II levels	Uncertain	[103]
SERPINs	C1 esterase inhibitor	Inhibition of the complement cascade by binding to C1r and C1s Inhibition of the contact activation system (intrinsic coagulation and kinin–kallikrein pathways) by binding to FXIIa and kallikrein	Uncertain	Clinicaltrials.gov NCT04530136 [259]
	Camostat mesylate	Inhibition of TMPRSS2	Uncertain	[7]
	Nafamostat mesylate	Inhibition of various serine proteases: thrombin, FXII, TMPRSS2, and kallikrein	Uncertain	[260]
Antimalarials	Hydroxychloroquine (HCQ)/chloroquine (CQ)	Inhibition of viral entry and endosome fusion/uncoating, reduction of cytokine production, and inhibition of platelet aggregation	Probably ineffective	[22, 23, 261, 262, 263, 264]
Blood‐derived products	Convalescent plasma	Neutralising antibodies from recuperated COVID‐19 patients	Probably ineffective	[265, 266, 267, 268]
	Hyperimmune immunoglobulin	Neutralising SARS‐CoV‐2 viral antigens by administering antibodies from recuperated COVID‐19 patients with high antibody titres	Uncertain	[269]
	REGN‐COV2	Cocktail of two neutralising antibodies against SARS‐CoV‐2 spike protein receptor binding domain	Uncertain	[270]
	Bamlanivimab	Anti‐spike neutralising IgG1 monoclonal antibody initially derived from a recovered COVID‐19 patient, intended for the treatment of mild to moderate COVID‐19	Promising	[271, 272]
Miscellaneous	Colchicine	Anti‐inflammation: inhibition of tubulin polymerisation, with effects on the inflammasome, cellular adhesion molecules, and inflammatory chemokines	Promising	[273]
	Vitamin D	Supports innate and adaptive immunity Inhibition of ADAM17 Counteracting NADPH oxidase activity resulting in decreased ROS production, thereby enhancing NO bioavailability Enhancing antioxidant enzymes that can scavenge free radicals Suppression of NF‐κB signalling and production of pro‐inflammatory cytokines	Vitamin D deficiency associated with COVID‐19; effect of supplementation inconclusive	[274, 275]
	Azithromycin	Potential antiviral activity, based on evidence from other RNA viruses	Uncertain	[276, 277, 278, 279]
	Sirolimus	Inhibition of mTOR pathway, which plays a role in pro‐inflammatory T‐cell differentiation	Uncertain	[280]
	Resveratrol	Reduction of leptin levels Suppression of Ang II Antioxidant effects Direct antiviral activity by inhibiting viral replication	Uncertain	[92, 281, 282, 283]
Heterologous vaccines	Influenza vaccine	Stimulation of trained innate immunity	Uncertain	[284, 285]
	BCG	Stimulation of trained innate immunity	Uncertain; no significant effect in frail elderly	[286, 287, 288]
	Measles vaccine	Stimulation of trained innate immunity	Uncertain	[289]