Mol. Cells

Molecular Perspectives of SARS-CoV-2: Pathology, Immune Evasion, and Therapeutic Interventions

Masaud Shah and Hyun Goo Woo

Additional article information


The outbreak of coronavirus disease 2019 (COVID-19) has not only affected human health but also diverted the focus of research and derailed the world economy over the past year. Recently, vaccination against COVID-19 has begun, but further studies on effective therapeutic agents are still needed. The severity of COVID-19 is attributable to several factors such as the dysfunctional host immune response manifested by uncontrolled viral replication, type I interferon suppression, and release of impaired cytokines by the infected resident and recruited cells. Due to the evolving pathophysiology and direct involvement of the host immune system in COVID-19, the use of immune-modulating drugs is still challenging. For the use of immune-modulating drugs in severe COVID-19, it is important to balance the fight between the aggravated immune system and suppression of immune defense against the virus that causes secondary infection. In addition, the interplaying events that occur during virus–host interactions, such as activation of the host immune system, immune evasion mechanism of the virus, and manifestation of different stages of COVID-19, are disjunctive and require thorough streamlining. This review provides an update on the immunotherapeutic interventions implemented to combat COVID-19 along with the understanding of molecular aspects of the immune evasion of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which may provide opportunities to develop more effective and promising therapeutics.

Keywords: COVID-19, immune escape, pathology, SARS-CoV-2, therapeutics


Coronaviruses (CoVs) infect a wide range of hosts, including mammals and avian species. They are, therefore, a hectic challenge not only to human health but also to livestock and the world economy. Species of human CoVs, including HCoV-OC43 and HCoV-229E, have long been known to cause minor respiratory infections such as common cold (Hamre and Procknow, 1966; McIntosh et al., 1967). Other species of CoVs, such as HCoV-HKU1 and HCoV-NL63, which cause similar seasonal infections, have recently been identified (van der Hoek et al., 2004). Moreover, the emergence of the highly pathogenic severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and SARS-CoV-2 over the past 20 years has made the CoVs even more challenging.

The outbreak of SARS-CoV and MERS-CoV infections resulted in the development of prophylactic and therapeutic interventions. However, since they were not pandemic, enough attention was not paid to eradicate them and effective treatments were not devised to cope with further emergencies. This, at least in part, led to the catastrophic outbreak of coronavirus disease 2019 (COVID-19) last year, which still awaits effective intervention. The whole genome sequence of SARS-CoV-2 was publicly available after the initial assessments, which accelerated the development of vaccines and therapeutics. CoV-related research has been conducted since the emergence of the avian infectious bronchitis virus (the first CoV), and later, HCoV-OC43 and HCoV-229E, leading to a better understanding of the replication of CoVs and their interactions with the host (Schalk and Hawn, 1931). The emergence of SARS-CoV and MERS-CoV further accelerated the basic understanding of the replicative cycle of these viruses as well as their host interactions (Prompetchara et al., 2020). The development of clinically effective interventions for the latest pandemic depends on the molecular characteristics, propagation, gene ontology, pathophysiology, and host receptors interaction of the SARS-CoV-2 (Sanders et al., 2020). This review provides an update on the immunotherapeutic interventions implemented to combat COVID-19 along with the molecular understanding of SARS-CoV-2, including its replication, immune evasion, basic pathophysiology, and interactions with the host.


Cell entry blockers

Over the last few months, we observed that SARS-CoV-2 is adapting to the host environment by rapidly mutating its S protein. The complementarity-determining regions of antibodies specifically recognize a conformational epitope on the antigen, where a single mutation in the hotspot residues could abrogate antibody-mediated S neutralization (Shah et al., 2020). This S-dependent host adaptability of the virus can put the whole development of neutralizing antibodies at risk. REGN-COV2 is a cocktail of two monoclonal antibodies (mAbs) of imdevimab and casirivimab, which have been designed to prevent the escape-mutants of SARS-CoV-2. REGN-COV2 has been evaluated for its safety, efficacy, and tolerability in phase I and II trials in adults (NCT04426695) and is currently undergoing phase III Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial. The cocktail has been found to be effective in ambulatory adult and pediatric COVID-19 patients (NCT04425629) (Weinreich et al., 2021). Although the individual antibodies in the REGN-COV2 cocktail bind to distinct and non-overlapping epitopes, a recent study has shown that a single amino acid mutation in the RBD could escape the antibody cocktail (Starr et al., 2021). These mutants are already presented in the circulating SARS-CoV-2 strains and are also found in the patients with persistent infection who have been treated with REGN-COV2 (Starr et al., 2021). Another S-neutralizing mAb, CT-P59 (Celltrion, Korea), has been shown to be safe for healthy subjects (NCT04525079) and is currently under clinical evaluation for the COVID-19 patients with mild to moderate symptoms (NCT04602000) (Kim et al., 2021). In addition, dozens of antibody-based therapeutics are under clinical investigation, including convalescent plasma, human mAbs VIR-7831 and LY-CoV555, and human polyclonal neutralizing antibody SAB-185 (Jiang et al., 2020; Weinreich et al., 2021; Zhou et al., 2021).

In addition, peptide biologics that block the S–ACE2 binding or S2–cell fusion may have great therapeutic potential, because all the SARS-CoV-2 variants utilize the same receptor and the fact that vaccines are only effective as a prophylactic agent for uninfected personnel. Recently, we identified short and structurally stable peptides those can abolish the S1–hACE2 interaction in vitro (data not published). Other groups implemented similar strategies and reported mini-proteins that effectively blocked S–ACE2 binding in pre-clinical investigations (Cao et al., 2020; Linsky et al., 2020).

Fusion blockers

The small peptide EK1 (OC43-HR2P) derived from HR2 motif has a potential to inhibit the fusion of CoVs by targeting the HR1 motif in the S2 subunit (Xia et al., 2019). EK1C4, derived from EK1, has shown to inhibit the fusion of the SARS-CoV-2 S-expressing pseudovirus as well as other lethal CoVs, including MERS-CoV and SARS-CoV (Xia et al., 2020b). On the contrary, S-neutralizing antibodies have been shown to be less effective against the fusion of SARS-CoV-2 S proteins (Shah et al., 2020; Tai et al., 2020), suggesting that the S-derived fusion blockers and ACE2-derived decoys eventually blocked the S–ACE2 interaction. Thymosin α1 (Tα1), a naturally occurring peptide, is not a fusion blocker, but can trigger the lymphocyte maturation and enhance the immune response by activating T cells. Administration of Tα1 can reduce the mortality of COVID-19 patients (Liu et al., 2020b). These results strongly support that the peptide-based biologics have great therapeutic potential for COVID-19.


RTC inhibitors

Three key enzymes, RNA-dependent RNA polymerase (RdRp), PLpro, and 3CLpro, make RTC a promising therapeutic target that can stop viral replication. RdRp is the core of the SARS-CoV-2 RTC and is involved in both replication and transcription, sharing ~95% similarity with that of SARS-CoV. Hence, anti-SARS-CoV RdRp drugs (remdesivir and favipiravir) have been evaluated for COVID-19 treatment. Remdesivir has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of adult and pediatric COVID-19 patients, owing to its efficacy in animal models of COVID-19 (Williamson et al., 2020) and in vitro viral inhibitory potential (Wang et al., 2020b). Remdesivir was shown to have some benefits in hospitalized patients who require supplemental oxygen; however, no clinical benefits were observed in patients who were on high oxygen supply and noninvasive and mechanical ventilation (Beigel et al., 2020; Williamson et al., 2020). In a multicenter randomized, blind trial conducted in China, the use of remdesivir showed no clinical benefits in mortality and viral clearance in COVID-19 patients (Wang et al., 2020d), although other studies reported better clinical outcomes (Spinner et al., 2020). In addition, favipiravir has been reported to eliminate the viral load, showing significant patient recovery (NCT04600999 and NCT04359615). Other members of the RTC, 3CLpro, or Mpro are equally important in combating viral propagation. For example, Mpro enzymatically releases other members of the RTC and structural entities of the virus (Kim et al., 2020). Researchers are now developing effective anti-3CLpro drugs by leveraging the substrate-specific knowledge of enzymes (Ma et al., 2020; Sacco et al., 2020).


Unlike SARS-CoV, which infects the lower respiratory tract, SARS-CoV-2 primarily targets the ACE2-expressing respiratory epithelial cells in the upper respiratory tract and later infects type I and type II pneumocytes and alveolar macrophages (Zeng et al., 2020). The extensive replication of SARS-CoV-2 leads to pyroptosis of the infected cells, releasing pro-inflammatory cytokines, danger-associated molecular patterns (DAMPs), and pathogen-associated molecular patterns (PAMPs) (Yap et al., 2020). These factors are detected by neighboring cells through pattern recognition receptors (PRRs), which further release a wave of pro-inflammatory cytokines, recruiting monocytes and T-lymphocytes to the infection site (Merad and Martin, 2020). Antigen presenting cells (APCs) display viral antigenic components to the CD4+ and CD8+ T cells, which further boost the viral specific humoral and T cell responses (Chen and John Wherry, 2020; Cox and Brokstad, 2020). These cellular and humoral immune responses are sufficient to fight and eliminate the infection (Fig. 3, right). However, like other viruses, SARS-CoV-2 utilizes its immune-masking strategies to escape the host immune response, resulting in severe immune complications.

Figure F3
RBC, red blood cell; NK cells, natural killer cells; TNF, tumor necrosis factor; IL, interleukins; CCL, chemokine (C-C motif) ligand; IFN, interferon; GM-CSF, granulocyte-macrophage colony-stimulating factor; ssRNA, single strand RNA; ...

As seen in SARS-CoV infection, a considerable loss of ACE2 function by SARS-CoV-2 infection can dysregulate the renin-angiotensin system, leading to an enhanced vascular permeability and an imbalance in the electrolyte and immune cell homeostasis (Kuba et al., 2005). This could partly be the reason for the higher mortality in older COVID-19 patients, as they are more susceptible to fluctuations in blood homeostasis (Bonanad et al., 2020). In about 20% of the infected patients with acute respiratory distress syndrome (ARDS), the hype in the cytokine profile was associated with an increase in levels of tumor necrosis factor (TNF), interleukin (IL)-6 and IL-7, chemokines (CCL2 and CCL3), and CXC motif chemokine ligand 10 (CXCL10). The patients with severe COVID-19 requiring intensive care exhibited higher levels of cytokines such as TNF, IL-2, IL-7, IL-10, and IL-1β (Huang et al., 2020). During active infection, T lymphocytes, particularly CD4+ T cells, were found to accumulate at infection site, which may be due to the infected APCs (Song et al., 2020). The activated TH1 cells released IFN-γ, TNF, and granulocyte-macrophage colony-stimulating factor (GM-CSF), which increased the levels of CD14+ and CD16+ monocytes at the infection sites in the patients with severe COVID-19 (Zhou et al., 2020).

The severity of COVID-19 is the result of uncontrolled viral replication, which leads to cytolysis and the release of aggravated cytokines. Typically, viral infection is cleared by cellular and humoral immune responses (Tay et al., 2020); however, uncontrolled rapid replication of the virus may trigger aggravated immune responses and paradoxically delay the IFN-I immune response, leading to ARDS approximately 8 to 9 days after the onset of symptoms (Grasselli et al., 2020). The patient’s condition can be further worsened by weak neutralizing antibodies against SARS-CoV-2 antigens, which leads to antibody-dependent enhancement of disease. The severity of the disease is reinforced by the infiltration of lymphocytes and monocytes into the inflamed lungs, resulting in lung collapse and death (Fig. 3, left).


Chloroquine (CQ) and hydroxychloroquine (HCQ)

Though known as antimalarial drugs, HCQ and CQ are widely used in the treatment of autoimmune disorders such as systemic lupus erythematosus or rheumatoid arthritis. CQ and its less toxic derivative HCQ have been repurposed, showing their therapeutic efficacy against SARS-CoV-2 in vitro (Wang et al., 2020b). In particular, HCQ was thought to be more efficient than CQ (Liu et al., 2020a); however, when tested at a clinically approved dosage, HCQ was not efficient in vitro (Kang et al., 2020). Many clinical trials have confirmed the ineffectiveness of HCQ in the treatment of COVID-19 (Rosenberg et al., 2020; Skipper et al., 2020); therefore, the FDA revoked the use of both CQ and HCQ in June 2020.

Dexamethasone and other corticosteroids

Dexamethasone was used in a RECOVERY trial, which revealed a substantial one-third decrease in mortality in patients on ventilators and one-fifth in patients on oxygen supply (RECOVERY Collaborative Group, 2021; WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group, 2020). Thus, the FDA has added dexamethasone sodium phosphate to its list of drugs that have been temporarily compounded during the COVID-19 pandemic to prevent supply disruption. Additionally, the World Health Organization has recommended corticosteroids, including hydrocortisone and prednisone, for the treatment of severe COVID-19 patients. There are some differences in the clinical efficacy of dexamethasone in patients with severe disease and in those who do not require air support. Severe patients who received dexamethasone for more than 7 days after the onset of symptoms were benefited, whereas the patients without severe inflammation did not respond well to the treatment, resulting in an increased mortality rate. The systemic use of corticosteroids can impair the clearance of the virus in SARS-CoV- and MERS-CoV-infected patients (Arabi et al., 2018; Lee et al., 2004); therefore, the use of dexamethasone in mildly infected patients may decrease the antiviral response and worsen the severity and mortality of the disease.


The induction of IFN-I response is vital for stimulating antiviral IFN-stimulating genes (ISGs) in both autocrine and paracrine modes. However, the results regarding the role of IFN-I and IFN-I response in the development of severe COVID-19 complications are contradictory. Peripheral blood evaluation of COVID-19 patients of varying severity has shown that the IFN-I response is significantly impaired in patients with severe COVID-19 (Hadjadj et al., 2020). In contrast, the transcriptome data of peripheral blood mononuclear cells and single-cell RNA-sequencing data of bronchoalveolar lavage fluid from COVID-19 patients showed the increased expression of various types of ISGs, pro-inflammatory cytokines, and chemokines (Wilk et al., 2020). Another study has demonstrated that the hyper-IFN-I response is associated with the TNF/IL-1β levels in severe COVID-19 but not in mild COVID-19 (Lee et al., 2020). IFN-I abolishes TNF tolerability in monocytes, macrophages, and animal models to respond to toll-like receptors (TLR) signals (Israelow et al., 2020). In patients with COVID-19, contradictory IFN-I responses can be attributed to the severity of the disease, the number of immune cells combating viral invasion and overcoming the inflammatory state, and the type and time of sample collection. This notion was addressed by a recent retrospective cohort study of 446 COVID-19 patients in China, wherein the early administration of IFN-α2b with or without umifenovir reduced mortality and accelerated patient recovery (Wang et al., 2020c). Moreover, IFN-β-based trials have shown promising results using a combination with the antiviral drugs (NCT04276688 and NCT04291729) or HCQ (NCT04350281) or a combination of an antiviral drug and HCQ (NCT04291729) (Bosi et al., 2020; Hung et al., 2020; Wang et al., 2020a). Furthermore, IFN-III-based clinical trials are ongoing to study how to overcome IFN-induced inflammatory effects and elicit effective antiviral responses (NCT04354259, NCT04343976, NCT04344600, and NCT04388709).

IL-6 inhibitors

Since the pathophysiology of COVID-19 overlaps with most of the complications in rheumatic diseases (Fajgenbaum and June, 2020), targeting the inflammatory pathways related to rheumatic diseases has been reported with some promising results in COVID-19 therapeutics. IL-6 is released at a considerably higher level in severe COVID-19 patients than in mild infection (Narayan et al., 2021). Inhibition of the IL-6 receptor (IL-6R) has been effective in relieving chronic rhinosinusitis (CRS) (Tanaka et al., 2016). Thus, the FDA has approved two classes of the IL-6 pathway inhibitors: one that blocks the IL-6R (e.g., tocilizumab and sarilumab) and others that block IL-6 itself (e.g., siltuximab). Tocilizumab has been approved by the FDA for CRS and rheumatologic disorders (Le et al., 2018). The administration of tocilizumab along with an off-label anti-retroviral protease inhibitor was effective against COVID-19 (Sciascia et al., 2020). Siltuximab, a recombinant mAb that binds to both soluble and membrane-bound IL-6, has shown promising clinical outcomes in patients with ARDS (NCT04322188). The combined use of siltuximab with anakinra and tocilizumab (NCT04330638) or normal saline (NCT04616586) is under evaluation, although the results have not been published yet. In contrast, other studies have shown that tocilizumab and sarilumab are not effective against COVID-19 (NCT04320615, NCT04327388, and NCT04315298).

IL-1R blockers

IL-1β is secreted by mature caspase-1 through the TLR-activated NLRP3 pathway loop, which further aggravates cytokine induction through IL-1R in an autocrine and paracrine manner. Anakinra, a recombinant IL-1R blocker used for the treatment of rheumatoid arthritis and cryopyrin-associated periodic syndromes (Cavalli and Dinarello, 2018), is currently being investigated in more than 10 clinical trials. Few studies have demonstrated that the administration of anakinra is safe and associated with the clinical improvement of COVID-19 (Cavalli et al., 2020; Huet et al., 2020).

Bruton’s tyrosine kinase (BTK) inhibitors

BTK relays the signaling of TLRs, IL-1R, CD19, BCR, CXCR4, and Fcγ-R1 (Pal Singh et al., 2018; Sharma et al., 2009), thus prompting studies on the use of BTK inhibitors against excessive host inflammation in severe COVID-19. The use of BTK inhibitors was further encouraged by the overlapping cytokine profiles of B-cell malignancies and chronic graft versus host disease (Dubovsky et al., 2014). The use of acalabrutinib was associated with the normalization of IL-6 and C-reactive protein (Roschewski et al., 2020). Ibrutinib is also currently undergoing two clinical trials (NCT04375397 and NCT04439006), and acalabrutinib has completed phase I and II randomized clinical trials (NCT04564040 and NCT04380688).


With the accumulation of comprehensive clinical data, the spectrum of effective therapeutics for the treatment of COVID-19 is rapidly growing and evolving, including therapeutics targeting cell entry, fusion, RTC production, and immune responses. In this review, we provide a concise update on the current therapeutic interventions for COVID-19 with perspectives on their molecular mechanistic targets (Table 1).

Table 1
Molecular targets and their therapeutic interventions for COVID-19

The pathogenesis of COVID-19 is driven by two main processes; the manifestation of disease is primarily driven by the rapid replication of the virus during the early course of infection, whereas the severity of the disease is driven by the exacerbated antiviral inflammatory response, which leads to tissue and organ damage. With respect to these, the use of antiviral therapies and IFNs in the early course of infection can provide optimal benefits. Antibody-based therapeutics against the viral S or other entities that can neutralize the virus will likely have the greatest benefit in the early stage of infection before the host immune system responds to the virus. During the late stage, the use of anti-inflammatory drugs and corticosteroids has more benefits, whereas their use in the early course of infection can interfere with the antiviral immune system. In the absence of specific and effective drugs that can block SARS-CoV-2 replication, immunomodulatory drugs can be used at this stage to save lives. Therefore, it is important to understand the cytokine profile, stage of the disease, comorbid pathological conditions, and other important immune-related factors before administering immunomodulatory drugs. Undoubtedly, future efforts to deepen our understanding of the molecular mechanisms of SARS-CoV-2 will provide opportunities to develop more effective and promising therapeutics.

Article information

Mol. Cells.Jun 30, 2021; 44(6): 408-421.
Published online 2021-06-1. doi:  10.14348/molcells.2021.0026
1Department of Physiology, Ajou University School of Medicine, Suwon 16499, Korea
2Department of Biomedical Science, Graduate School of Ajou University, Suwon 16499, Korea
Received February 1, 2021; Accepted March 25, 2021.
Articles from Mol. Cells are provided here courtesy of Mol. Cells


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Figure 1

(A) SARS-CoV-2 particles are spherical (60 to 140 nm in diameter) with spike proteins (S) protruding from the surface of virion. The S is densely glycosylated by O- and N-linked glycans (green color) that potentially mask the immunogenic nature of the S protein during infection. The S1 domain of S anchors the virus to the host cells, and the S2 domain of S establishes membrane fusion. TMPRSS2 and furin cleave the S1 domain of S, thereby priming the S2 domain for membrane fusion. (B) The virus is engulfed through endocytosis or the direct membrane fusion at the cell surface. After S1 cleavage, S2 domain undergoes conformational re-arrangement and exposes fusion peptides (FPs) for anchoring into the host cell membrane; the HR1 and HR2 motifs fold and bring the viral and host membrane close for fusion. HE, hemagglutinin-esterase; M, membrane protein; N, nucleocapsid; E, envelope; NTD, N-terminal domain; RBD, receptor-binding domain; HR, heptad repeat; RBM, receptor-binding motif; TM, transmembrane; CP, cytoplasmic domain; TMPRSS2, trans-membrane protease, serine 2.

Figure 2

(A) The ORF1a and ORF1b are transcribed into pp1a and pp1ab; the latter is transcribed as the result of –1 ribosomal frameshift at the overlapping point between IRF1a and ORF1b. Nsp3 (PLpro) cleaves pp1a at three points (red arrows), and Nsp5 (3CLpro) releases nsp4–nsp16 by cleaving pp1a and pp1ab (green arrows). (B) Following membrane fusion, the viral RTC members generated by pp1a and pp1ab are involved in the biogenesis of ROs (left). The SARS-CoV-2 proteins antagonizes IFNs (red lines) (right). ORF, open reading frames; S, spike; E, envelope; M, membrane; N, nucleocapsid; ssRNA, single strand RNA; sgRNA, subgenomic RNA; gRNA, genomic RNA; dsRNA, double strand RNA.

Figure 3

RBC, red blood cell; NK cells, natural killer cells; TNF, tumor necrosis factor; IL, interleukins; CCL, chemokine (C-C motif) ligand; IFN, interferon; GM-CSF, granulocyte-macrophage colony-stimulating factor; ssRNA, single strand RNA; dsRNA, double strand RNA; RIG-I, retinoic acid-inducible gene I; MDA5, melanoma differentiation-associated protein 5; NLRP3, NLR family pyrin domain containing 3; DAMPs, danger/damage associated molecular pattern; PAMP, pathogen associated molecular pattern; MAVS, mitochondrial antiviral signaling protein; TLR, toll-like receptor; ERGIC, endoplasmic-reticulum–Golgi intermediate compartment; DMV, double membrane vesicle; DMS, double membrane spherules; RTC, replication and transcription complex; ADE, antibody-dependent disease enchantment; MHC, major histocompatibility complex; CXCL, chemokine (C-X-C motif) ligand; HLA, human leukocyte antigen; ASC, apoptosis-associated speck-like protein containing a CARD; CTL, cytotoxic lymphocytes.

Table 1

Molecular targets and their therapeutic interventions for COVID-19

Category Target Drug/biologic Trials ID Phase
Cell entry blockers ACE Arbidol NCT04260594 Phase 4
rhACE2 APN01 NCT04335136 Phase 2
rbACE2 NCT04375046 Phase 1
Spike REGN-COV2 (REGN10933 + REGN10987) Placebo NCT04425629 NCT04426695 NCT04452318 Phase 2 Phase 3
XAV-19 NCT04453384 Phase 2
CT-P59 Placebo NCT04602000 Phase 2
SAB-185 Normal Saline NCT04469179 NCT04468958 Phase 1 Phase 2
VIR-7831 Placebo NCT04545060 Phase 2 Phase 3
VIR-7831 BRII-196/BRII-198 LY3819253 Remdesivir Placebo NCT04501978 Phase 3
LY3819253 LY3832479 Placebo NCT04427501 NCT04497987 NCT04634409 Phase 2 Phase 3 Phase 2 Phase 2
Fusion blockers TMPRSS2 Nafamostat mesilate NCT04390594 NCT04418128 Phase 3 Phase 2 Phase 3
Nafamostat mesilate Placebo NCT04352400 Phase 2 Phase 3
Nafamostat mesilate TD139 Standard care NCT04473053 Phase 2 Phase 3
RTC inhibitors RdRp Remdesivir Standard care NCT04292899 NCT04292730 Phase 3
Remdesivir Placebo NCT04280705 Phase 3
Favipiravir Standard care NCT04542694 NCT04600999 Phase 3
Favipiravir Hydroxychloroquine NCT04359615 Phase 4
IFN IFNR Interferon β-1b NCT04465695 Phase 2
IFNR/3CLpro/immune system Hydroxychloroquine Lopinavir/ritonavir Interferon β-1a Interferon β-1b NCT04343768 Phase 2
IFNR/RdRp Interferon β-1b Remdesivir NCT04647695 Phase 2
IFNR/RdRp Lopinavir/ritonavir Ribavirin Interferon β-1b NCT04276688 Phase 2 Phase 3
Interferon α-2b Rintatolimod NCT04379518 Phase 1 Phase 2
Interferon α-1b Thymosin α1 NCT04320238 Phase 3
Peginterferon λ-1A Placebo NCT04354259 NCT04343976 NCT04344600 NCT04388709 Phase 2
Cytokines inhibitors IL-6R Tocilizumab Placebos NCT04356937 Phase 3
Tocilizumab NCT04331795 Phase 2
Tocilizumab NCT04363736 Phase 2
Tocilizumab Placebos NCT04320615 Phase 3
Tocilizumab Anakinra NCT04339712 Phase 2
Sarilumab NCT04327388 Phase 3
Sarilumab Placebos NCT04315298 Phase 2 Phase 3
Sarilumab NCT04661527 Phase 2
Sarilumab NCT04359901 Phase 2
Siltuximab NCT04329650 Phase 2
Siltuximab NCT04330638 Phase 3
IL-1 Anakinra Tocilizumab NCT04339712 Phase 2
Anakinra NCT04443881 Phase 2 Phase 3
Anakinra Placebos NCT04680949 Phase 3
Anakinra Tocilizumab Standard care NCT04412291 Phase 2
Anakinra NCT04357366 Phase 2
Anakinra Standard care NCT04643678 Phase 2
Anakinra Normal saline NCT04362111 Phase 3
Anakinra Tocilizumab Siltuximab NCT04330638 Phase 3
BTK Anakinra NCT04148430 Phase 2
Acalabrutinib NCT04564040 NCT04380688 Phase 1 Phase 2
Ibrutinib NCT04375397 NCT04665115 Phase 2
Corticosteroids Immune suppressor Dexamethasone Hydroxychloroquine NCT04347980 Phase 3
Dexamethasone (IV, nasal) NCT04513184 Phase 2
Dexamethasone NCT04509973 Phase 3
Dexamethasone  Methylprednisolone  NCT04603729 Phase 3
Dexamethasone  Methylprednisolone  NCT04499313 Phase 3
Dexamethasone NCT04395105 Phase 3
Dexamethasone Remdesivir Baricitinib Placebo NCT04640168 Phase 3
Dexamethasone (early) Dexamethasone (late) NCT04530409 Phase 4
NA-831 NA-831 & atazanavir NA-831 & dexamethasone Atazanavir & dexamethasone NCT04452565 Phase 2 Phase 3
Corticosteroids Dexamethasone Tocilizumab NCT04476979 Phase 2
CQ and HCQ TLRs/NLRs HCQ 40 trials are withdrawn or terminated, 52 are completed, and ~100 studies are active
CQ 3 trials are terminated and few are active