Table 1.
Therapeutic strategies of drugs under active investigation based on the target site and mechanism of action for Covid-19.
| Drug | Class (Pharmacology/Chemical) | MOA | Clinical trial | Reference |
|---|---|---|---|---|
| 1. Drug interfering with the fusion of the virus with host cells | ||||
| Apilimod | Interleukin inhibitor | Inhibits lipid kinase PIKfyve (phosphoinositide kinase for position 5 containing a FYVE finger domain) in cellular regulation | Phase II | [165] |
| Camostat | Serine protease inhibitor | Blocks mechanism of SARS-CoV-2 which uses TMPRSS2 for docking to the ACE2. This hampers the binding of the spike protein of the virus to the host cell | Phase 1 | NCT:04321096[166,167] |
| Nafamostat | Serine protease inhibitor | Phase II | NCT:04321096[32,104] | |
| Tranexamic acid | Antifibrinolytic hemostatic | Inhibits activation of plasminogen thereby reducing the conversion of plasminogen to plasmin (fibrinolysin), an enzyme that degrades fibrin clots. Plasmin acts on coronavirus and cleaves the newly inserted furin site at the S protein portion. This results in increased virulence and infectivity. | Phase II | NCT:04338126[168] |
| Umifenovir | Antiviral | The antiviral properties are thought to occur due to interactions with aromatic residues within the viral glycoproteins involved in S protein /ACE2 membrane fusion and cellular recognition. | Phase IV | NCT:04260594[169] |
| 2. Drugs targeting RAAS-ACE2-AT-1 receptor | ||||
| rhACE2 (APN01) | Recombinant enzyme | The biologic is known to possess a dual mode of action. Firstly, it mimics human enzyme ACE2 misleading viruses to bind to a pseudo receptor; secondly, it reduces inflammatory reaction during infection, thus protecting against lung infection. | Phase II | NCT:04335136;04287686 (withdrawn) [[170], [171], [172], [173]], |
| Ang (1-7) | Cardioprotective angiotensin peptide | ACE2-Ang (1-7)-Mas receptor axis. It limits several detrimental effects of Ang II on AT-1 receptors by triggering counter-regulatory protective effects through binding to G protein-coupled Mas receptors. It is being explored clinically, for example, for stimulating hematopoietic recovery in patients with cancer after chemotherapy and for examining cardiovascular effects. |
Phase II/III | NCT:04332666[171,174,175] |
| Captopril Trandolapril Perindopril Fosinopril Benazepril Quinapril Ramipril |
ACE inhibitor |
Currently, these drugs are approved for the treatment of hypertension. By preventing the cleavage of Ang I to Ang II, Ang I levels are increased resulting in the increased formation of Ang (1-9) by ACE2 and subsequently Ang (1-7). Nonclinical studies have demonstrated that these drugs upregulate ACE2 expression by decreasing the availability of Ang II at the AT-1 receptor and subsequently masking the inhibitory activity of ADAM17 on ACE2 | Phase II | NCT:04355429[176] |
| Phase IV | NCT:04330300[177,178] | |||
| Phase II | NCT:04366050[179] | |||
| Losartan Valsartan Telmisartan |
AT-1 receptor blocker | All of the ARBs are approved for the treatment of hypertension. They reversibly and competitively inhibit Ang II binding to the AT-1 receptor. This action prevents Ang II-AT-1 receptor-mediated cytokine release. Preclinical studies have demonstrated that blockade of AT-1 receptors increases ACE2 expression by inhibiting ADAM17 that cleaves ACE2. Losartan is an inverse agonist. The PPAR partial agonist activity of telmisartan also contributes to increased ACE2 expression. | Phase II | NCT:04312009; NCT:04311177[[180], [181], [182]] |
| Phase IV | NCT:04335786[[180], [181], [182]] | |||
| Phase II | NCT:04355936[183] | |||
| Simvastatin (In combination with Ruxolitinib) |
Anti-hyperlipidemic | The drug is known to inhibit virus multiplication in early stages, decreases virus-induced cytotoxicity in affected host cells, along with inhibition of Rab/RhoA GTPase activity and LC3 membrane localization known to enhance the replication process in viruses. It also affects cytokine storm by decreasing pro-inflammatory cytokines (TNF-α, IL-6, INF-γ) released during the viral infection. | Phase II | NCT:04348695[184,185] |
| Atorvastatin | Anti-hyperlipidemic | The drug is known to inhibit virus multiplication in the early stages, along with decreasing the virus titer in infected cells, thus increasing host cell viability. | Phase II | NCT: 04380402 [184,186] |
| 3. Drug interfering with translocation of the virus within host cells | ||||
| Chloroquine phosphate HCQ |
Antimalarial | Approved or the treatment of rheumatoid arthritis and systemic lupus erythematosus. Targets endocytosis and endosomes of host cells. Disrupts intracellular trafficking and viral fusion events by increasing the pH in vacuoles. Additionally, the virus requires acidic pH for proper Golgi apparatus functioning and transport. It inhibits glycosylation of ACE2 receptors. Additionally, immunomodulatory effects through inhibition of cytokine production, autophagy, and lysosomal activity in host cells are reported. | Phase II | NCT:04303507[187] |
| Hydroxychloroquine sulfate and azithromycin | Antimalarial and antibiotic | HCQ Same mechanism as chloroquine; Azithromycin binds to 50s subunit of the ribosome and interferes with translation and prevents the expression of the replicase gene. | Phase II | NCT:04370782[188] |
| 4. Drugs interfering with proteolysis mechanism of the virus within host cells | ||||
| Danoprevir (in combination with ritonavir) | Antiviral | Interferes with the protease of virus and inhibits the release of genomic material from the virus to host cell. | Phase II | NCT: 04291729[38] |
| Ritonavir + Lopinavir | Antiretroviral | Ritonavir and Lopinavir decrease the viral load by inhibiting viral protease 3CLpro, target nucleocapsid during virion assembly, and also, target tumor necrosis factor receptor type 6. Ribavirin inhibits viral RNA-dependent RNA polymerase but is less potent than remdesivir. Interferon strengthens the innate immune system. | Phase II | NCT:04321174[131,189] |
| Ritonavir/Lopinavir and interferon-β1b | Antiviral | Phase II | NCT:02845843[131,189] | |
| Ribavirin + Ritonavir + Lopinavir | Antiviral | Phase II | NCT:04276688[190] | |
| Darunavir (with Cobicistat) | Antiretroviral | Prevents HIV replication through binding to the viral protease, inhibits cleavage of encoded viral protein Gag-Pol. Also, it targets nucleocapsid during virion assembly. Cobicistat (a CYP3A inhibitor) enhances the activity of darunavir. | Phase III | NCT:04252274[191] |
| Carmofur (1-hexylcarbamoyl-5-fluorouracil) | Anticancer agent | In vitro studies have shown carmofur inhibits potently the main protease Mpro activity. | None | [134] |
| 5. Drugs interfering with replication, transcription, and translation of virus genomic material | ||||
| Favipiravir | Antiviral | Inhibition of viral coded enzyme RNA-dependent RNA polymerase would block the formation of a negative-sense RNA strand during viral replication within the host cell. | Phase III | NCT:04336904[192] |
| Galidesivir (BCX4430) | Antiviral | Phase II | NCT:03891420[193] | |
| Remdesivir | Antiviral | Phase III | NCT:04292730[194] | |
| Levovir | Antiviral | Phase II | NCT:04347915[195] | |
| Emtricitabine + Tenofovir | Non-nucleoside reverse transcriptase inhibitor + Nucleotide reverse transcriptase inhibitor | This drug class is widely recommended as first-line treatment for HIV when co-administered with two nucleoside or nucleotide reverse transcriptase inhibitors. These drugs compete with deoxycytidine 5'-triphosphate for reverse transcriptase enzyme. | Phase III | NCT:00458393[196] |
| Ciclesonide | Glucocorticoid | It interacts with viral non-structural protein 15, either directly or indirectly leading to inhibition of viral replication of coronavirus. | Phase II | NCT:04330586[197,198] |
| Nitazoxanide | Broad-spectrum antiviral agent, anthelminthic | Approved for the treatment of diarrhea. It suppresses viral replication by inhibition of viral hemagglutinin maturation achieved by inhibition of viral transcription factor immediate-early 2 and activating eukaryotic translation initiation factor 2α (an antiviral intracellular protein). It is purported to induce the host immune response to produce interferons by the host’s fibroblasts. | Phase IV | NCT:04341493[170] |
| Selinexor | Anticancer | It is a selective inhibitor of nuclear export, blocks cellular protein XPO1. | Phase II | NCT:04349098[199] |
| Ivermectin | anti-parasite | Inhibit viral replication by inhibiting IMPα/β1-mediated nuclear import of viral proteins. | Alone: no; With Bicalutamide: Phase II | NCT:04373824; NCT:04374279[200] |
| 6. Drugs interfering with cytokine storm syndrome and compromised immune Function | ||||
| Tocilizumab | Anti-inflammatory | It is approved to treat rheumatoid arthritis. It alleviates inflammation of the lungs by suppressing cytokine storm (reduces IL-6 and TNFα). | Phase II | NCT: 04335071[196,197] |
| Sarilumab | Anti-inflammatory | Phase III | NCT:04327388[201] | |
| Siltuximab | Anti-inflammatory | NA | NCT: 04322188[202,203] | |
| Ruxolitinib | Anticancer | Inhibit the mediation of cytokine and growth factor signaling by inhibiting JAK 1 and 2, which otherwise affect immune function and hematopoiesis. | Phase II | NCT:04331665, 04334044[204] |
| Baricitinib | Anticancer | It selectively and reversibly inhibits tyrosine-protein kinase Janus associated kinases 1 and 2 to modulates their signalling pathways, thereby reduce the phosphorylation and activation of STATs leading to inhibition of cytokine and chemokine transcription and thereby modulate the immune response. Currently, it is approved for the treatment of rheumatoid arthritis. Also, a clinical trial in combination with remdesivir has been initiated. | Phase III | NCT: 04320277, NCT: 04340232, NCT:04321993[152] |
| Sirolimus (Rapamycin) | Immunosuppressant | It inhibits T lymphocyte activation and proliferation in response to antigenic and cytokine. It also inhibits the mammalian target of rapamycin pathway to block viral protein expression and virion release. | Phase II | NCT: 04341675[205] |
| L-ascorbic acid | Antioxidant | It affects the development and maturation of T-lymphocytes, in particular, Natural Killer cells involved in the immune response to viral agents. Also, it inhibits ROS production in cases of the systemic inflammatory syndrome. | Phase I | NCT: 04323514[206,207] |
| Piclidenoson | Anti-inflammatory, A3 adenosine receptor agonist | Targets A3 Adenosine receptor leading to deregulation of the Wnt/β-catenin pathway. Inhibits inflammatory cytokine release syndrome in cancer immunotherapy. | Phase II | NCT:04333472[208] |
| Methylprednisolone | Glucocorticoid, Anti-inflammatory, immunomodulator | It activates a specific type of nuclear receptors, leading to their reformed gene expression thus inhibiting cytokine production and decreases circulating lymphocytes, inhibits TNF-α expression and NF-κB activation. | Phase II, III | NCT:04273321, NCT: 04263402, NCT:04323592[58] |
| Thalidomide | Anti-angiogenic, anti-inflammatory, anti-fibrotic | It impairs the synthesis of TNF-alpha and reduces the infiltration of inflammatory cells, proinflammatory cytokine, and chemokine levels, and inhibits the activated p-NFκBp6. | Phase II | NCT: 04273581, NCT:04273529[209] |
| NORS (Nitric Oxide Releasing Solution) | Gasotransmitter, Endothelium-derived relaxing factor (EDRF) | The inhibitory effect is shown to be correlated with s-nitrosylation of viral proteins such as reductases and proteases, thus inhibiting viral protein and RNA synthesis. NO generated by inducible nitric oxide synthase inhibits the virus replication cycle. | Phase II | NCT:04337918[210] |
| Colchicine | Antigout, Anticancer | Colchicine inhibits tubulin polymerization and microtubule generation and, possibly, effects on cellular adhesion molecules, inflammatory chemokines, and the inflammasome. It reduces excessive inflammatory reaction by inhibiting the activation of NLRP3 inflammasome and inhibit the synthesis of TNF-α and IL-6. | Phase II | NCT:: 04328480, NCT: 04326790, NCT:04322682[154] |
| Pyridostigmine Bromide | Acetylcholinesterase inhibitor | It inhibits acetylcholinesterase thereby improves acetylcholine (ACh) bioavailability. ACh then binds nicotinic-alpha receptors present in macrophages and T cells. This action reduces overactivated immune cells, which reduces inflammatory mediators and elevates CD4+ T cell counts. In experimental studies, it is shown to reduce inflammation and mortality. | Phase II | NCT:04343963[211,212] |
| Acalabrutinib | Anticancer | It is undergoing a Phase III trial for the treatment of mantle cell lymphoma and chronic lymphocytic leukemia. It selectively inhibits Bruton Tyrosine Kinase and thereby reduces the production of inflammatory cytokines associated with respiratory complications. | Phase II, Phase III | NCT:04346199[213] |
| Vazegepant (BHV-3500) | Calcitonin gene-related peptide (CGRP) receptor antagonist | Upon viral attack, Transient Receptor Potential channels on the plasma membrane are activated and release CGRP, which subsequently release interleukin 6 and pro-inflammatory mediators. This results in the development of cough, fever, migraine, and pain. Vazegepant blocks the CGRP receptor-mediated effects. | Phase II | NCT:04346615[214] |
| Tradipitant | Neurokinin1 receptor antagonist | It is indicated in the treatment for patients with atopic dermatitis. It prevents the activation of NK1 receptor by Substance P. | Phase III | NCT:04326426[215] |
| Etoposide, Teniposide (chemically related) | Anticancer | Both appear to act by causing breaks in DNA via interaction with DNA topoisomerase II or by the formation of free radicals. Teniposide is more potent as regards the production of DNA damage and cytotoxicity. The drugs are proposed to treat the cytokine storm in Covid-19 associated with the hyperinflammatory response to the virus. | Phase II | NCT:04356690[216] |
| 7. Drugs purported to prevent Covid-19 progression in patients with severe ARDS | ||||
| Nitric oxide Gas | Gasotransmitter | It reverses pulmonary hypertension and improves the condition of severe hypoxia thereby shortening the length of ventilatory support. | Phase II | NCT:04290871[217] |
| Sevoflurane | Anesthetic agent | It attenuates ARDS by vascular dilation, improves oxygenation in ventilator patients, thus decreases morbidity and mortality of patients. | Phase II | NCT:04355962[218] |
| Fingolimod | Immunomodulator | It is under clinical trial for treating multiple sclerosis. Structurally, it resembles lipid sphingosine-1-phosphate (S1P). It is a potent functional antagonist of S1P1 receptors in lymph node T cells. It suppresses the exit of lymphocytes from lymph node T cells, thus reducing the inflammation and attenuates immunopathogenesis. In Covid-19 patients, it is known to decrease pulmonary edema and hyaline membrane formation, thus preventing ARDS associated with the disease. | Phase II | NCT:04280588[219] |
| Fluvoxamine | Anti-depressant | It inhibits the uptake of 5-HT by blood platelets and brain synaptosomes. It is under trial to prevent more severe complications like shortness of breath in Covid-19 patients. | Phase II | NCT:04342663[101] |
| Tetrandrine | Anti-inflammatory and anti-tumor | It shows broad pharmacologic effects with antitumor and apoptotic activity. It decreases division and maturation of fibroblasts, that slows down lung damage in patients. | Phase IV | NCT:04308317[68] |
| Aviptadil (FDA Orphan Drug) |
Vasoactive intestinal polypeptide (VIP) analogue | Inhibits NMDA-induced caspase-3 activation, IL6 and TNF-α production in lungs. | Phase II | NCT:04311697[220] |