key: cord-0721420-ux9ngtdu
authors: Tarighi, Parastoo; Eftekhari, Samane; Chizari, Milad; Sabernavaei, Mahsa; Jafari, Davod; Mirzabeigi, Parastoo
title: A review of potential suggested drugs for coronavirus disease (COVID-19) treatment
date: 2021-01-20
journal: Eur J Pharmacol
DOI: 10.1016/j.ejphar.2021.173890
sha: d5edffc21282cab38f2bf9a7815d0f30f1501f8c
doc_id: 721420
cord_uid: ux9ngtdu

The latest pandemic, coronavirus disease-2019 (COVID-19), is associated with high prevalence and easy transmission, which is expanding globally with no conventional treatment or vaccine. The new virus revealed 79% and 50% genomic similarities with severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV), respectively. Accordingly, since the disease resists testing and adopting new therapeutics, repositioning pre-existing drugs may present a fast and attractive strategy with known safety, characteristics, and dosage used. However, they are not specific and targeted. Therefore, several drugs have been investigated for their efficacy and safety in the treatment of COVID-19; most of them are undergoing clinical trials. This article summarizes clinical investigations of potential therapeutic drugs used as COVID-19 therapy. Subsequently, it prepares a pattern of results and therapeutic targets to help further experiment designs. We have investigated drugs as classified in the following three groups; 1) The drugs which computationally showed effectiveness (in silico) but needed further lab confirmations; 2) Emetine, Teicoplanin, and Nelfinavir have shown effectiveness in vitro; 3) The drugs currently under clinical trial.

protease of SARS-CoV-2 have introduced Nelfinavir as the best candidate with the most binding 6 free energy (Xu et al., 2020b) . 7 Furthermore, studies on SARS-CoV have revealed that Nelfinavir has strongly inhibited SARS-8 CoV replication, lowering viral antigens significantly. Nelfinavir is also very safe, with mild 9 diarrhea as a side effect in 15-20% of patients (Yamamoto et al., 2004) . Therefore, an in vitro 10 study evaluated its efficacy on SARS-CoV-2. The findings revealed that Nelfinavir could 11 effectively inhibit SARS-CoC-2 replication in vitro. This study suggested Nelfinavir Teicoplanin, a glycopeptide antibiotic, blocks the cathepsin L, located in the late endosome. 4 Cathepsin L mediates the cleavages of viral S protein, which leads to the virus-host cell fusion 5 and viral genome released into the cytoplasm. Therefore, blocking this mechanism would 

active agent against Zika and Ebola viruses. Azithromycin is a common therapy for many 1 chronic lung diseases, including chronic obstructive pulmonary disease (COPD), asthma, 2 interstitial lung diseases, bronchiectasis, and cystic fibrosis (La Scola et al.; Martinez et al.) . 3 Thus, in studies, it has been suggested as the right candidate for co-treatment with 4 Hydroxychloroquine for COVID-19. In an in vitro study on Vero E6 cells, the concentration of 5 1, 2, and 5 µM of Hydroxychloroquine and 2, 5, and 10 µM for Azithromycin were used. They combined with 500 mg of Azithromycin on the first day, then 250 mg daily for the following 10 four days. The viral RNA load was decreased rapidly. All the combinational group participants 11 were virologically cured on day 6. The majority of patients, 81.3%, were favorably discharged They can also interfere with nucleic acid replication, viral protein glycosylation, virus assembly, 10 and release. Notably, Chloroquine has an immune-modulatory activity, which may enhance its 11 antiviral effects synergistically (Ponticelli and Moroni, 2017). However, its utilization is 12 restricted because of its potential overdose, acute poisoning, and death. Hydroxychloroquine is a 13 derivative of Chloroquine, which has been demonstrated to be much less toxic (̴ 40%) (Liu et al., 14 2020a). It is known for its clinical safety profile. Meanwhile, both effectively treat many 15 inflammatory diseases such as rheumatoid arthritis and lupus by inhibiting cytokine (IL-1 and Hydroxychloroquine for five days significantly reduced the fever recovery time and cough 1 duration compared to standard treatments (Chen et al., 2020d). 

Anakinra is a 17 kD biological recombinant, non-glycosylated human interleukin-1 receptor 13 antagonist with a short half-life of approximately 3-4 hours and an acceptable safety profile to 14 neutralize hyperinflammatory-related to COVID-19 with the severe respiratory syndrome. IL-1 15 plays a significant role in stimulating the production of inflammatory cytokines and TNFα. g/day) for seven days. Prophylaxis of thromboembolism was considered for all cases. Some 1 patients were a candidate for an intravenous bolus 500 mg dose of methylprednisolone. This 2 study determined a notable decrease in the demand for admission to the Intensive Care Unit, 3 invasive mechanical ventilation, and mortality compared with standard of care. More patients 4 experienced elevated liver enzymes in the Anakinra group than the control group (Huet et al., 5 2020). A previous study exhibited improved respiratory system and reduced serum C-reactive 6 protein in 72% of patients with a high-dose of Anakinra (IV) in severe COVID-19, ARDS, and 7 hyper inflammation (Cavalli et al., 2020 ). An open-label study recruited nine patients with 8 moderate to severe pneumonia results from COVID-19. Only an old patient exhibited an acute 9 respiratory failure after Anakinra that led to discontinuing the treatment and ICU admission.

Other patients revealed good clinical and biological outcomes, in which C reactive protein (CRP) 11 levels reduced at day 6 in all cases and controlled in 5 at day 11. Chest CT scan showed hospitalization, including ≥65 years of age, underlying chronic medical condition. It has been 1 emphasized on prompt administration of Bamlanivimab within ten days of symptom onset or 2 following a positive test. It should be noticed that this medication has not an authorization of use 3 in patients with COVID-19 related hospital admission or need for oxygen therapy. 4 Bamlanivimab is manufactured as a single dose aqueous solution vials in 700 mg/20 ml for 5 intravenous infusion over 60 minutes (https://www.fda.gov/media/143603/download; Bamlanivimab at a dose of 2800 mg vs. placebo. Hospitalization, emergency department visits, 14 or death within 28 days of treatment was significantly lower than those in placebo (Chen et al., 15 2020). Any benefit has not been found in hospital admitted patients 16 (https://www.niaid.nih.gov/news-events/statement-nih-sponsored-activ-3-trial-closes-ly-cov555- 17 sub-study). In this regard, the efficacy and safety of Bevacizumab have been assessed in a single-arm trial. with non-significant clinical improvement and die compared to control at day 28. There was no 10 correlation between IL-6 serum concentration and the other clinical outcome predictors. Time to 11 the normalization of C reactive protein levels was significantly shorter with Sarilumab. Icatibant binds to B2 receptors and hinders bradykinin functionality (Farkase., 2016). 6 It is revealed that COVID-19 enters the host cells through binding to the ACE2 receptor, highly 7 expressed on pulmonary cells. Following virus activity, the ACE2 receptors will be occupied, 8 and active ACE2 will reduce in the body, subsequently, and of note, ACE2 is responsible for 9 hydrolyzing the active bradykinin metabolite [des-Arg973] (DABK). Therefore, as a side effect, 10 COVD-19 activates this bradykinin system, which leads to fluid extravasation and leukocyte 11 recruitment to the lung, which persists in pulmonary edema subsequently. This will deteriorate 12 the lung damages caused by the virus. Thus, it seems that targeting the bradykinin system may be Careful interpretation of these findings needs to perform further randomized clinical studies. Ivermectin is also a safe drug, which is a study of phase 3 clinical trials on dengue patients in 19 Thailand; it was introduced to be secure enough (Caly et al., 2020) . Also, in a meta-analysis 20 working on its high doses, its safety was strongly confirmed even beyond its prescribed doses information. Theoretically, these drugs would exhibit targeted effects, but the procedure may last 17 several years, which is not appropriate for a pandemic. where antivirals are the most used, which all are summarized in Table 1 . Table 2 summarized the 5 physical and chemical properties and structure of these agents. 6 Remdesivir is the only drug that WHO has issue its emergency use authorization. Darunavir, 7 Oseltamivir, and Arbidol showed no improvement and was introduced as ineffective. Notably, 

Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-2 controlled, multicentre trial

Oseltamivir (Tamiflu®) and its 5 potential for use in the event of an influenza pandemic

Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by 9 computational methods

Clinical Characteristics of Imported Cases of COVID-19

Effective treatment of severe COVID-19 patients with tocilizumab

In vitro antiviral activity and projection of optimized dosing design of 13 hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 14 (SARS-CoV-2)

The place for remdesivir in COVID-19 treatment

52S)-2-[(2R,3R,4R,5S,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-22-amino-5,15-dichloro-64-[(2S,3R,4R,5S,6R)-3-(decanoylamino)-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-26

4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-3,5,6