Table 1.
Summary of some clinical features involving drugs reviewed in the present work against SARS-COV-2.
| Drugs | Mechanisms of Action/Targets | Some clinical features |
EC50 (µM) | CC50 (µM) | References | ||||
|---|---|---|---|---|---|---|---|---|---|
| aClinical Trial ID | Interventions | Control | Study Design (Phase/Location /Enrolment No.) | Summarized Outcomes | |||||
| Combined Therapies | |||||||||
| Lopinavir-Ritonavir | Lopinavir and ritonavir areprotease inhibitors, which block viral replication, Ritonavir is a CYP3A inhibitor which functions primarily to reduce the metabolism of lopinavir, thereby boosting lopinavir levels. | NCT04343768 | Hydroxychloroquine + Lopinavir/Ritonavir + Interferon Beta-1A (in first group) and + Interferon Beta-1B (in second group) | Hydroxychloroquine + Lopinavir/Ritonavir | Randomized (Completed/Iran /60) | No results on clinical outcomes with the full protocol as provided by WHO and National clinical trial on outcome measures but the phases completed. | 26.63 | [26], [58], [149] | |
| Ribavirin | Ribavirin, a guanosine analogue inhibits viral RNA polymerase and mRNA capping. | NCT04276688 | Lopinavir/ritonavir 400 mg/100 mg twice daily for 14 days + Ribavirin 400 mg twice daily for 14 days + Interferon Beta-1B 0.25 mg subcutaneous injection alternate day for 3 days | Lopinavir/ritonavir 400 mg/100 mg twice daily for 14 days | Randomized (Completed/ HongKong/127) | Three combinations were safe and superior to Lopinavir–Ritonavir alone and shortening virus shedding, alleviating symptoms, and facilitating discharge of patients with mild to moderate COVID-19 | 109.50 | >400 | [150], [32], [151] |
| Arbidol | Arbidol inhibits by interfering with multiple steps of the virus replication cycle. The stages of SARS-CoV-2 replication targeted by arbidol is during the virus entry process, the post-entry stages, or the entire process of infection (Full-time). Arbidol efficiently blocked both viral entry and post-entry stages. | NCT04476719 | Atafenovir 200 mg KAPSUL (Capsules containing 207.009 mg Umifenovir hydrochloride monohydrate equivalent to 200 mg Umifenovir hydrochloride. | Arbidol 100 mg KAPSUL (Capsules containing 103.504 mg Umifenovir hydrochloride monohydrate equivalent to 100 mg Umifenovir hydrochloride | Open-label, Randomized, Single oral dose, two-period, cross over. (Phase 1/Turkey /18) | To assess the bioequivalence of atafenovir 200 mg Kapsul In comparison with Arbidol 100 mg Kapsul in healthy male subjects under fasting conditions alongside with ethical protocols and strong confidence intervals evaluation. | 4.11 | 31.79 | [32] |
| Direct antiviral (Monotherapy) | |||||||||
| Favipiravir | RNA-dependent RNA polymerase (RdRp) inhibitor. Blocking the replication of other RNA viruses. Activated into its phosphoribosylated form (favipiravir-RTP) in cells, which then inhibits viral RNA polymerase activity | NCT04336904 | Day 1: 1800 mg, BID; Day 2 – 14: 600 mg, TID | Placebo Dosage: Day 1: 1800 mg, BID; Day 2 and thereafter: 600 mg, TID, for a maximum of 14 days. | Multi-centre, randomized, double-blind, placebo-controlled (1:1) Phase 3 (Italy/100) | This is a multi-centre, randomized, double-blind, placebo-controlled (1:1) clinical study to explore the efficacy and safety of Favipiravir in the treatment of adult subjects with COVID-19-moderate type. | 61.88 | >400 | [18], [150] |
| Remdesivir | Remdesivir is a nucleotide analogue with the triphosphate form i.e., RDV-TP being used as a substrate for many viral RNA-dependent RNA polymerase (RdRp) complexes. RDV-TP has been reported to inhibit the viral RNA synthesis via a specific mechanism of delayed chain termination for coronaviruses including SARS-CoV-2 RdRp. It has been observed that RDV-TP specifically resembles Adenosine triphosphate (ATP) molecule and competes with the nucleotide during the viral RNA synthesis. | NCT04292899 | Standard of care with and without mechanical ventilation + Remdesivir Administered as an IV for 5 and 10 days separately (RDV 200 mg Day 1 and 100 mg from Day 2–5 or 2–10 according to the grouping) | Standard of care | Randomized completed (USA/4891) | The magnitude of benefit cannot be determined because there was no placebo control, however, the most common adverse events noticed were nausea worsening respiratory failure, elevated alanine aminotransferase level, and constipation. | 0.77 | >100 | [151], [152] |
| Atazanavir | Atazanavir is of high interest because of its bioavailability within the respiratory tract. ATV could dock in the active site of SARS-CoV-2 Mpro, with greater strength even than Lopinavir. ATV inhibits SARS-CoV-2 replication, alone or in combination with ritonavir (RTV) in Vero cells, human pulmonary epithelial cell line, and primary monocytes, impairing virus-induced enhancement of IL-6 and TNF-α levels. | NCT04452565 | NA-831 (60 mg orally twice a day for one day, followed by 30 mg once a day for four consecutive days (Five days in total)) and Atazanavir (400 mg orally twice a day for one day, followed by 200 mg daily for four consecutive days (five days total)) | NA-831 60 mg orally twice a day for one day, followed by 30 mg once a day for four consecutive days (Five days in total) | Randomized Controlled Phase 2/3 (USA/525) | Currently recruiting in the Phase 2/3 trial to evaluate four treatment strategies for non-critically ill hospitalized participants(not requiring ICU admission and/or mechanical ventilation)with SARS CoV-2 infection, in which participants will receive NA-831 or Atazanavir with or without Dexamethasone. | [153] | ||
| Indirect antiviral | |||||||||
| Hydroxychloroquine (HCQ) | Hydroxychloroquine exhibits antiviral potency by inhibiting virus entry into host cells. The pathway can be related to post-translation alteration of newly synthesized proteins via glycosylation inhibition | NCT04328285 | HCQ 200 mg: 2 tablets on the evening of Day 1 and 2 tablets on the morning at Day 2 and 1 tablet once daily afterwards | Placebo of HCQ, 2 tablets on the evening on Day 1, and 2 tablets on the morning at Day 2 and 1 tablet once daily afterwards. | Randomized, double-blinded, placebo-controlled. Phase 3 (France/ 600) | In a placebo-controlled trial, lopinavir is being compared to hydroxychloroquine, which is used to treat malaria, rheumatoid arthritis, and lupus erythematosus, as a preventative treatment for COVID-19 in exposed health-care workers with the primary outcome being the occurrence of the infection (NCT04328285) | 0.72 | [52], [154] | |
| Omacetaxine (Homoharringtonine) | No clear mechanism of action recorded against SARS-CoV-2 but its actions in other viruses implicates ribosomal bond to prevent protein translation | N/A | N/A | N/A | N/A | Clinical investigation is required to ascertain its mechanism of action and the ideal dose against SARS-Co-2 | 2.10 | 59.75 | [58], [73], [127] |
| Emetine dihydrochloride | Prevention of DNA and RNA replication in Vero E6 cells. | A broad-spectrum antiviral drug with in vitro activity against MERS-CoV at an EC50 of 0.34 µM | Used in combination with Remdesivir and the nucleoside analogue GS-5734 to exhibit synergistic inhibitory effect against SARS-CoV-2 replication | Use for the treatment of generality of viral infection. | 0.50 (Reduction in viral RNA) 0.46 (Reduction in infectious viruses) | 56.46 | [58], [155] | ||
| Presatovir | Inhibition of fusion intercellular mediated by the F protein | NCT02135614 | Randomize, double-blind, placebo-controlled studies Phase 2b clinical trial | Used against the respiratory syncytial virus (RSV) resistance development and treatment | [156] | ||||
| Chloroquine (CQ) | Chloroquine as Hydroxychloroquine earlier described exhibits its antiviral potency equally by inhibiting virus entry into host cells. The pathway can be related to post-translation alteration of newly synthesized proteins via glycosylation inhibition Chloroquine is also proposed to inhibit the glycosylation of ACE2 receptor chains, thus limiting ligand recognition of these receptors, rendering the viral spike protein unable to mediate cell entry. | NCT04342650 | CQ 450 mg twice daily (3 tablets of 150 mg, every 12 h) on day 1, followed by CQ 450 mg once daily (3 tablets of 150 mg) from D2 to D5. Oral administration. | 150 mg placebo tablets (oral) | Randomized completed (Brazil/152) | The preliminary findings from the Clinical trial suggest that a higher dosage of CQ in COVID-19 should be carefully administered because of safety concerns regarding QTc prolongation and its potential safety hazards | 1.13 | >100 | [151], [154], [157], [158] |
| Antibiotics (combined therapies) | |||||||||
| Azithromycin | Azithromycin in combination therapy with hydroxychloroquine Inhibits endosomal acidification via early endosomal pathway | NCT04329832 | Azithromycin 500 mg on day 1 plus 250 mg daily on days 2–5 (maybe administered intravenously per clinician preference). If the patient has already received azithromycin before randomization (no more than 2 days), the prior doses will count toward the 5-day total. | N/A | Randomized Phase 2 (USA/85) | A formalized protocol for trials with Bayesian statistical evidence approached currently ongoing. Statistical approach contributes to the network of meta-analyses of therapeutics of COVID-19 | 2.12 | [53], [86], [158] | |
| Ivermectin | The hypothesized mechanism of action is through inhibiting IMPα/β1-mediated nuclear import of viral proteins by dissociation of the heterodimer which is the same for other RNA viruses. | NCT04343092 | Ivermectin 12 mg /weekly) + Hydroxychloroquine 400 mg/daily + azithromycin 500 mg daily (Ivermectin 0.2 mg /kg (single dose at once = 2 tablets of 6 mg/weekly) | N/A | Pilot Randomized completed (Iraq/100) | This study showed that adding IVM to HCQ and AZT had a better cure rate and shorter time to stay in the hospital compared with controls but it was relatively safe without observable safety signals. results are needed to be validated in a larger prospective follow up study | [104] | ||
| Colchicine | Microtubule polymerization inhibitor by binding with the beta-tubulin subunit to prevent it from assembling (Tubulin-colchicine complex). Also, it inhibits Monosodium urate (MSU), as well as the inhibitory effect on neutrophil functions. | NCT04392141 | Oral administration of Colchicine + Herbal Phenolic Monoterpene Fractions | N/A | Randomized Phase 2 (Iran/200) | No significant results yet but it’s an ongoing oral administration with some herbal phenolic monoterpene fractions will be added to standard treatment in patients with COVID-19. | [159] | ||
| Immuno-stimulants | |||||||||
| Transmembrane Protease Serine2 (TMPRSS2) inhibitor | The inhibitors block viral activity by preventing TMPRSS2′s action on S protein processing (inhibit SARs-CoV-2 entry into the host cell). | NCT04509999 | Bicalutamide 150 mg oral tablet daily at 1:1 randomization for up to 4 weeks | Standard of care and placebo | Randomized Phase 3 (USA/100) | The study is an ongoing clinical trial that proposes to test bicalutamide at 150 mg oral daily dosing in a double-blind placebo-controlled randomized trial in male patients with early symptomatic COVID-19 disease | [160] | ||
| Interferon (IFNs) | Type I and III IFNs are broad-spectrum antivirals both direct inhibitory effects on viral replication in the upper airway, reducing viral spread to the lungs and transmission, and supporting an immune response to clear virus infection. | NCT04389645 | IP-10 in CDS protocol. Dynamic IP-10 measurements in hospitalized COVID-19 positive patients | N/A | ObservationalCompleted (Israel/52) | The longitudinal and real-time IP-10 measurements could help with personalizing immunomodulatory treatment regimens for COVID-19 patients and may support better patient outcomes. | [161], [162], [163] | ||
| Teicoplanin and other glycoprotein drugs (Dalbavancin, oritavancin, and telavancin) | Teicoplanin exhibits antiviral activity in the early stage of the viral life cycle of viruses such as Ebola virus, MERS-CoV, and SARS-CoV via inhibition of the low-pH cleavage of the viral spike protein by host cell’s cathepsin L and cathepsin B in the late endosomes thereby preventing the release of viral RNA and replication. | NCT04492501 | Assessing efficacy and safety of standard treatment including steroids, Remedisvir, Tocilizumab, mesenchymal stem cell therapy therapeutic plasma exchange in addition to standard treatment as well in combination with convalescent Plasma with other investigational treatments inlined with standard treatment Operational Definitions | Interventional retrospective case-control, single centre-based cohort study | An open-label Phase II Non-randomized (Pakistan/600) | Investigators will use different investigational treatment as mono or in combination to see mortality and morbidity benefit based on the limited evidence available so far. These investigational modalities include Therapeutic plasma exchange (TPE), Convalescent Plasma (CP), Remdesivir, Tocilizumab, and Mesenchymal stem cell (MSC) therapy in addition to standard supportive treatment. | 8.78 concentration reached for a daily dose of 400 mg which is higher than 1.66 μM to inhibit 50% of viruses (IC50) in vitro | [159], [163] | |