Current status of potential therapeutic candidates for the COVID-19 crisis

Abstract

As of April 15, 2020, the ongoing coronavirus disease 2019 (COVID-2019) pandemic has swept through 213 countries and infected more than 1,870,000 individuals, posing an unprecedented threat to international health and the economy. There is currently no specific treatment available for patients with COVID-19 infection. The lessons learned from past management of respiratory viral infections have provided insights into treating COVID-19. Numerous potential therapies, including supportive intervention, immunomodulatory agents, antiviral therapy, and convalescent plasma transfusion, have been tentatively applied in clinical settings. A number of these therapies have provided substantially curative benefits in treating patients with COVID-19 infection. Furthermore, intensive research and clinical trials are underway to assess the efficacy of existing drugs and identify potential therapeutic targets to develop new drugs for treating COVID-19. Herein, we summarize the current potential therapeutic approaches for diseases related to COVID-19 infection and introduce their mechanisms of action, safety, and effectiveness.

Keywords: ACE2 blocker; Antimalaria; Antiviral: Chinese traditional medicine; COVID-19; Immunoenhancer; Monoclonal antibody; Vaccine.

Fig. 1

SARS-CoV-2 infection-induced impairment of multiple organ function Impairment of multiple organ function by SARS-CoV-2 infection includes acute respiratory distress syndrome (ARDS), acute cardiac injury, acute kidney injury, acute liver injury, neurological injury, gastrointestinal injury, immune system injury, and coagulation impairment. Abbreviations: ALT, alanine transaminase; APTT, activated partial thromboplastin time; ARDS, acute respiratory distress syndrome; AST, aspartate aminotransferase; CK-MB, creatine kinase myocardial band; CNS, central nervous system; FDP, fibrinogen degradation products; HLA-DR, human leukocyte antigen DR; INR, international normalized ratio; LDH, lactate dehydrogenase; MYO, myoglobin; NK, natural killer cell; NT-proBNP, N terminal pro-B-type natriuretic peptide; PaO2/FiO2, oxygenation index; PNS, peripheral nervous system; PT, prothrombin time; RAAS, renin-angiotensin-aldosterone system; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; TBIL, total bilirubin; Th, helper T cell; TNI, troponin I.

Fig. 2

The hypothetical replication cycle of SARS-CoV-2 and the possible targets of anti-COVID-19 drugs. SARS-CoV-2 binds to the ACE2 receptor on the surface of cells using the Spike protein, which subsequently triggers endocytosis. On releasing the viral nucleocapsid to the cytoplasm, encapsidated positive-strand genomic RNA [(+)gRNA] serves as a template to translate polypeptide chains, which are cleaved to non-structural proteins including RNA-dependent RNA polymerase. The single negative strand RNA [(-)gRNA] synthesized from (+)gRNA template is employed to replicate more copies of viral RNAs. Subgenomic RNAs (sgRNAs) are synthesized by discontinuous transcription from the (+)gRNA template and then encode viral structural and accessary proteins, which are subsequently assembled with newly synthesized viral RNA to form new virions. The nascent virions are then transported in secretory vesicles to the plasma membrane and released by exocytosis. RhACE2, convalescent plasma and JAK inhibitor baricitinib could dampen the binding of the Spike protein on the surface of the SARS-CoV-2 to ACE2 expressed on the cell surface. Lopinavir/ritonavir and favipiravir inhibit the proteolysis of polypeptide chains. Remdesivir inhibits RNA-dependent RNA polymerase. EIDD-2801 could inhibit SARS-CoV-2 replication. NO and Zinc might inhibit SARS-CoV-2 replication. Vitamin D might induce antimicrobial peptides to reduce SARS-CoV-2 replication. Ivermectin could effectively block SARS-CoV-2 growth. Baricitinib could interrupt the passage of SARS-CoV-2 entering cells through inhibition of AAK1-mediated endocytosis. CQ and HCQ inhibit virus/cell fusion process. LHQW and IFNs could block the process of virus replication (RNAs transcription, protein translation, and post-translational modification). Abbreviations: AAK1, adaptor-associated kinase 1; CQ, chloroquine; ER, endoplasmic reticulum; HCQ, hydroxychloroquine sulfate; IFNs, interferons; iNO, inhaled nitric oxide; JAK, janus kinase; LHQW, Lianhua Qingwen; rhACE2, recombinant human angiotensin-converting enzyme 2; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Fig. 3

The hypothetical mechanisms of SARS-CoV-2 infection-induced cytokine storm and antiviral immunity and the possible therapeutic targets of patients with COVID-19 infection. “Cytokine storms” might start with inflammatory cytokine secretion into lung tissue and pulmonary blood vessels from virus-infected alveolar epithelial cells, pulmonary vascular endothelial cells, alveolar macrophages, multinucleated giant cells, and other infiltrated immune cells, which mainly serve to limit the replication and spreading of the virus and to induce downstream immune responses via the blood circulation. Following the recruitment and activation by primary cytokines, systemic immune cells (neutrophils, DCs, Mo-Mφ, NK cells, CD4⁺ T cells, CD8⁺ T cells, Th1 cells, Th2 cells, and Th17 cells, etc.) further secrete inflammatory cytokines and promote the cascade of inflammatory processes to eliminate virus and virus-infected cells. Vitamin C might inhibit SARS-CoV-2 and alleviate the illness by decreasing inflammatory cytokines, stimulating IFN production, supporting lymphocyte proliferation, boosting the phagocytic capability of neutrophils, monocytes, and macrophages, protecting lung barrier function and reducing lung vascular injury, increasing IFN secretion from alveolar Mφ, Mo-Mφ, DCs, NK cells, and CD8⁺ T cells. IFNs could enhance NK cell cytotoxicity, enhance expression of major histocompatibility complex Ⅰ proteins, and promote the production of IFNs and the proliferation of NK cells and Mφ. Bevacizumab could reduce vascular permeability. Vaccines (mRNA1273, Ad5-nCoV, PittCoVacc, and NVX-CoV2373) could induce protective antiviral immune memory, while MSCs could decrease pro-inflammatory cytokines, promote regeneration, secrete multiple paracrine factors and anti-inflammatory cytokines, and enlarge the proportion of Treg cells. iNO could alleviate pulmonary hypertension through its selective pulmonary vasodilation. Corticosteroids, LHQW, Xuebijing, IVIG, tocilizumab, sarilumab, baricitinib, vitamin D, CQ, and HCQ could also reduce inflammation. Heparin blocks the thrombus formation. Abbreviations: AT I, type I alveolar epithelial cell; AT Ⅱ, type Ⅱ alveolar epithelial cell; CQ, chloroquine; DC, dendritic cell; G-CSF, granulocyte-colony stimulating factor; HCQ, hydroxychloroquine sulfate; IFN-γ, interferon gamma; IL, interleukin; iNO, inhaled nitric oxide; IP-10, interferon-inducible protein-10; IVIG, intravenous gamma globulin; LHQW, Lianhua Qingwen; MCP-1, monocyte chemotactic protein 1; MIP-1A, macrophage inflammatory protein-1a; Mo-Mφ, monocyte-macrophage; MSCs, mesenchymal stem cells; NK, natural killer cell; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; Th, helper T cell; TNF-α, tumor necrosis factor alpha; Treg, regulatory T cell.