In late December 2019, a novel flu-like human coronavirus, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2 or COVID-19), was identified as the cause of a series of pneumonia cases in Wuhan, Hubei Province in China (1, 2). The outbreak has rapidly spread, resulting in an epidemic throughout China, as well as other countries around the world. On March 12th 2020, the World Health Organization (WHO) announced the outbreak of COVID-19 as a pandemic (3).
Prevalent symptoms at the beginning of the disease were fever, cough, myalgia, chills, dyspnea and pneumonia. Less common Symptoms include humor, headache, hemoptysis and diarrhea (4). COVID- 19 also made troubles such as acute respiratory distress syndrome, RNAaemia, acute heart damage, and secondary infection in patients (5). In patients with CoVID-19, the number of white blood cells can vary. Leukopenia, leukocytosis, and lymphopenia are reported problems, although lymphopenia is the most common of all. It is notable that the increased levels of aminotransferase have also been presented in some COVID-19 patients (6).
Because the SARS-CoV and SARS-CoV-2 are very similar, the biochemical interactions and the pathogenesis are likely to be similar (7). The delivery of virus particles into the host cell needs the virus to bind to the angiotensin-converting enzyme 2 (ACE-2) receptors in the type II pneumocytes in the lungs and form a viral endosome through a clathrin-mediated endocytosis (8–10). When the SARS spike protein, a homotrimer of S proteins, binds to the type I integral membrane receptor ACE-2, a pH-independent endocytotic reaction occurs (11, 12). When internalized, the fusion of virus with lysosomes occurs depending on the low endosomal and lysosomal pH (13). Endosomal proteases cathepsin B and L splitted S-glycoprotein into S1 and S2 domains that S2 causes membrane fusion (14). Cathepsin B and L activity is prevented when endosomal pH increased. Viral entrance into the cytoplasm is also dependent on an acidic endosomal pH (15). After releasing the virus into the cytosol, a viral RNA-dependent RNA polymerase is utilized to run the viral replication, exocytosis of virions, and spread to neighboring cells (16). Binding of the SARS-CoV to the ACE-2 receptors triggers an inflammation cascade in the lower respiratory tract. Infection of human cells by SARS-CoV causes inflammatory cascade by virus-infected antigen-presenting cells (APCs). APCs presenting the outsider antigen to CD4+-T-helper (Th1) cells, and releasing interleukin-12 to further motivate the Th1 cell that stimulate B-cells to produce antigen-specific antibodies (17). Although these mechanisms may proceed differently in the novel SARS-CoV-2, the intermediate host of SARS-CoV2 is not known yet. However, few approved prophylactic or therapeutic drugs for COVID-19 diseases are available. Some therapeutic agents are used off-label, alone or in combination. There are several possible suggestions to treat this disease: (1) Inhibitors of viral replication such as Ribavirin, Remdesivir, Favipiravir, Emtricitabine/tenofovir, (2) Inhibitors of viral proteases such as Lopinavir/ritonavir (LPV/r), Darunavir, Danoprevir, Atazanavir, Cobicistat, Noscapine, (3) Inhibitors of viral entry to the host cell such as Chloroquine/hydroxychloroquine, Arbidol, Baricitinib, Ruxolitinib, Recombinant human ACE2, Bromhexine, (4) Immune enhancement agents such as Interferon‑alpha (α)‑1b/2b, Interferon‑beta (β), Programmed cell death 1 (PD‑1) blocking antibody, Levamisole, (5) Immunomodulating agents such as Intravenous immunoglobulin, Fingolimod, Thalidomide, (6) Immunosuppressive agents such as Glucocorticoids, (7) Anti‑inflammatory agents such as Tocilizumab, Sarilumab, Siltuximab, Eculizumab, Tetrandrine, NSAIDs, (8) Pulmonary vaso‑effectors such as Nitric oxide, Sildenafil, Aviptadil, Bevacizumab, Losartan, (9) and other drugs such as Carrimycin and Mepolizumab (18).
Chloroquine (CQ) sulfate and Chloroquine phosphate are classified as anti-malarial drugs. Hydroxychloroquine (HCQ) is used for both anti-malarial activity and for autoimmune diseases like rheumatoid arthritis and systemic lupus erythematosus as well (19). The suggested mechanism for anti-viral activity of CQ in SARS-CoV2 is to target low endosomal pH (acidification) required for virus cell fusion, and to interfere with cellular receptors glycosylation. CQ/HCQ also targets the entrance of extracellular zinc to intracellular lysosomes where it interferes with RNA-dependent RNA polymerase activity and replication of coronavirus (20). The molecular mechanism of CQ/HCQ is to inhibit the cytokine storm by suppressing activation of T cells (21). HCQ has shown more potency than CQ against SARS-CoV2, in vitro (22). Gastrointestinal effects, like vomiting and diarrhea, are the most common adverse effects of HCQ and CQ (21). Other less common side effects including muscular weakness, diplopia, dyskinesia, seizures, myasthenic syndrome, sleeplessness, agitation, psychosis, depression, anxiety, and confusion have also been shown (23). Retinopathy and cardiomyopathy are the severe side effects caused by using the drug for a long time (21).
Levamisole as a synthetic low molecular weight compound belonging to the anti-helminthic class of medications can enhance the cellular immunity based on dosage and timing of its clinical administration (24, 25). A previous study had reported that a combination of levamisole and ascorbic acid therapy in-vitro can reverse the depressed helper/inducer subpopulation of lymphocyte in measles virus. The abnormality in lymphocytes could be reproduced by Levamisole treating of normal lymphocytes with measles virus in-vitro. Thus, this compound could also be considered as a suggestive drug for COVID-19 treatment (25, 26).