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| Author | Year | Method | Detail of method | Name of compound/drug | Target | Efficacy | Comments |
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| Lei et al. [318] | 2020 | In vivo | BALB/c mice to determine the pharmacokinetic profiles of the fusion proteins | A recombinant protein by connecting the extracellular domain of human ACE2 to the Fc region of the human immunoglobulin IgG1 | Spike protein | The IC50 values of ACE2-Ig for SARS-CoV and SARS-CoV-2 neutralization were 0.8 and 0.1 μg·ml−1, respectively. Desirable pharmacological properties in mice | Potential applications in the diagnosis, prophylaxis, and treatment of SARS-CoV-2 |
| Rathnayake et al. [319] | 2020 | In vivo | Old male hDPP4-KI mice infected with MERSMA-CoV | Dipeptidyl and tripeptidyl series of compounds | Main protease | 7a, 6c, 7e, 7h, and 6j: EC50 values ranging from 0.15 to 0.9 μM in Vero E6 cells, IC50: 0.17 to 0.82 μM. 40% of mice treated with compound 6h survived, and all mice treated with compound 6j were alive at the end of the study | 6j resulted in the survival of MERSMA-CoV-infected hDPP4-KI mice |
| Schäfer et al. [320] | 2020 | In vivo | An immune-competent mouse model of COVID-19 by remodeling the SARS-CoV-2 S RBD at the mACE2-binding interface. Human Ace2-expressing HT1080 cells and Syrian hamster model of SARS-CoV-2 | Human mAbs (hu-mAbs) | Reduction in viral load and prevent infection | Neutralizing hu-mAbs targeting SARS-CoV-2 promotes reduction in viral load and prevent infection in macaques and hamsters effective dose: 5.3 and 16 mg/kg inhibitory concentration (IC)50/IC90 (half-maximal/90% IC) of 4.4/18 to 26/140 ng/ml | |
| Schumann et al. [321] | 2020 | In vivo | Female C57Bl/6 mice, LPS stimulation | MP1032:5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt | Immune-modulating | Direct inhibitory activity on human PARP-1 was detected in the low micromolar range (IC50 = 1.55 μM). MP1032 works as a ROS scavenger, reduced the secretion of TNF-α and IL-6. MP1032 pre-treatment significantly reduced plasma cytokine levels compared with vehicle-treated mice by 50% (TNF-α) and 25% (IL-6). Significant reduction in SARS-CoV-2 replication | MP1032 could further attenuate prolonged virus replication by preventing oxidative stress or by limiting ADP ribosylation of the viral nucleocapsid protein via PARP-1 inhibition |
| Shang et al. [322] | 2021 | In vivo | African green female hACE2 transgenic mice, SARS-CoV-2 injection RNA extraction and qPCR, RNA in situ hybridization assay, histopathological examination | Endosomal acidification inhibitors, including chloroquine, bafilomycin A1, and NH4CL | Antiviral actions against SARS-CoV-2 | (40 μM), bafilomycin A1 (100 nM), and NH4CL (12.5 mM) suppressed the replication of SARS-CoV-2 in all cell types chloroquine (60 mg·kg−1) and bafilomycin A1 (0.1 mg·kg−1) markedly reduced virus yields in lung tissues. Alleviated viral pneumonia in hACE2 transgenic mice | Endosomal acidification inhibitors exhibited antiviral actions against SARS-CoV-2 |
| Sheahan et al. [323] | 2020 | In vivo | Male and female 20- to 29-week old SPF C57BL/6J (Stock 000664 Jackson Labs) mice, whole-body plethysmography 50, 150, or 500 mg/kg EIDD-2801 2 hr prior to intranasal infection with 5E + 04 PFU of mouse-adapted SARS-CoV | Ribonucleoside analog β-d-N4-hydroxycytidine | Antiviral efficacy against the three most recently emerged human CoV: SARS-CoV, MERS-CoV, and SARS-CoV-2 | Bioavailable NHC prodrug (β-d-N4-hydroxycytidine-5′-isopropyl ester), improved pulmonary function and reduced virus titer and body weight loss | Continued development of EIDD-2801 as a potent broad-spectrum antiviral |
| Tai et al. [324] | 2021 | In vivo | Sprague Dawley rats. (i) HCQ‐IV: 12 rats received a single dose of 0.590 mg HCQ sulfate per animal via IV injection; (ii) HCQ‐IT: 20 rats received a single dose of 0.590 mg HCQ sulfate per animal via intratracheal (IT) administration; and (iii) liposomal HCQ‐IT: 20 rats received a single dose of 0.284 mg liposomal HCQ sulfate per animal via IT administration 0.25, 1, 4, 24, and 72 hours postdose and for tissue/organ samples were 0.25, 4, 24, and 72 hours postdose | Inhalable liposomal hydroxychloroquine (HCQ) | Pharmacokinetic study | Compared with unformulated HCQ administered intravenously, liposomal HCQ showed higher (∼30-fold) lung exposure, longer (∼2.5-fold) half-life in lungs, but lower blood exposure with ∼20% of peak plasma concentration (Cmax) and 74% of area under the curve from 0 to 72 hours (AUC 0–72) and lower heart exposure with 23% of Cmax and 58% of AUC 0–24 (normalized for dose) | Inhalable liposomal HCQ may provide clinical benefit and serve as a potential treatment of COVID-19 |
| Tortorici et al. [325] | 2020 | In vivo | From two individuals recovering from severe COVID-19 disease. Surface plasmon resonance (SPR) and flow cytometry. Cell-cell fusion assay using VeroE6 cells/Syrian hamster model | Human neutralizing antibodies (S2E12 and S2M11) | Against SARS-CoV-2 | IC50 values were 1.2 to 6.6 ng/ml to protect hamsters against SARS-CoV-2 challenge competitively block angiotensin-converting enzyme 2 (ACE2) attachment and that S2M11 also locks the spike in a closed conformation by recognition of a quaternary epitope spanning two adjacent receptor-binding domains | Antibody cocktails for prophylaxis or therapy |
| Wahl et al. [326] | 2021 | In vivo | Coronavirus replication in human lung-only mice (LoM) and histopathologic analysis LoM were administered EIDD-2801 starting 24 h or 48 h post-SARS-CoV-2 exposure and every 12 h thereafter | Ribonucleoside analog β-D-N4-hydroxycytidine (NHC): oral prodrug EIDD-2801 (also known as molnupiravir or MK-4482) | Inhibited SARS-CoV-2 replication | EIDD-2801 pre-exposure prophylaxis significantly reduced virus titers in the human lung tissues of LoM by over 100,000-fold in two independent experiments | Prophylactic administration EIDD-2801 is highly effective |
| Wang et al. [327] | 2021 | In vivo | Male hACE2 mice inoculated intranasally with SARS-CoV-2 stock virus rhesus macaque model of SARS-CoV-2 infection | Screening the FDA-approved peptide drug library with LibDock | Against SARS-CoV-2 | Ten polypeptide drugs were selected. Dalbavancin showed the strongest inhibitory ability. (EC50) was ∼12 nM. Significant inhibition of SARS-CoV-2 pseudovirion entry into HEK293/hACE2 cells, with an IC50 of ∼53 nM in both mouse and rhesus macaque models, viral replication, and histopathological injuries caused by SARS-CoV-2 infection are significantly inhibited by dalbavancin administration | Dalbavancin directly binds to human angiotensin-converting enzyme 2 (ACE2) with high affinity, thereby blocking its interaction with the SARS-CoV-2 spike protein |
| Weston et al. [328] | 2020 | In vivo | Mice were inoculated intranasally with SARS-CoV | 20 FDA-approved drugs | Against SARS-CoV-2 | 7 of these inhibit SARS-CoV-2 at non-cytotoxic concentrations. Many of the compounds have IC50 under 10 μM, chloroquine and chlorpromazine did not inhibit viral replication in mouse lungs based on viral titers recovered at 4 dpi neither drug inhibited viral replication in the lungs, but both protected against clinical disease | |
| White et al. [329] | 2021 | In vivo | A human ACE2-expressing adenovirus to transduce the naturally resistant wild-type BALB/c mice and sensitize them to SARS-CoV-2 infection, K18-hACE2 mouse model | eEF1A inhibitor plitidepsin (aplidin): targeted the eukaryotic translation machinery | Inhibited SARS-CoV-2 replication | IC90 of 1.76 nM: Vero E6 IC90 of 0.88 Nm: human cell line significantly reduced genomic RNA content reduction of nearly 2 log units in SARS-CoV-2 viral titers in the lungs of the 0.3 mg/kg plitidepsin group, reduction of 2 log units in viral lung titers at day 3, similar to two daily 50 mg/kg doses of remdesivir | Plitidepsin as a host-targeted anti-SARS-CoV-2 agent with in vivo efficacy |
| Wu et al. [330] | 2020 | In vivo | 10 male C57BL/6 mice related to 200 mg/kg/day GB-2 everyday by oral administration. immunohistochemistry (IHC) assessment | GB-2, the formula from Tian Shang Sheng Mu of Chiayi Puzi Peitian Temple: in Taiwan: the index compound of Camellia sinensis var. assamica extract | The protein and mRNA expression of ACE2 and TMPRSS2 | No mouse death and no significant alteration in mouse activity or body weight (IHC) data revealed that the expression levels of both ACE2 and TMPRSS2 were markedly diminished in the GB-2 group compared with the control group 50 μg/mL of theaflavin could inhibit protein expression of ACE2 and TMPRSS2 | GB-2 and theaflavin could act as potential compounds for ACE2 and TMPRSS2 inhibitors |
| Yuen et al. [331] | 2021 | Ex vivo | Human lung tissues were treated with the indicated drugs overnight, followed by SARS‐CoV‐2 infection at 2 × 106 PFU/well | Small molecules targeting the ULK1/Atg1 complex involved in the induction stage of autophagy (ULK1 inhibitor SBI0206965), the ATG14/Beclin1/VPS34 complex involved in the nucleation step of autophagy (class III PI3‐kinase inhibitor VPS34‐IN1), and a widely used autophagy inhibitor that persistently inhibits class I and temporary inhibits class III PI3‐kinase (3‐MA) and a clinically approved autophagy inhibitor that suppresses autophagy by inhibiting lysosomal acidification and prevents the formation of autophagolysosome (HCQ) | Target the key cellular factors involved in key steps of the autophagy pathway | Not all the tested autophagy inhibitors suppressed SARS-CoV-2 infection inhibition of class III PI3‐kinase Vps34 downstream of ULK1, in contrast to inhibition of ULK1, which caused a significant decrease in SARS‐CoV‐2 replication (EC50) of HCQ was 19 μM, that of Vps34‐IN1 was 0.82 μM Vps34‐IN1 potently inhibited SARS‐CoV‐2 viral replication in normal ex vivo human lung tissue culture in a dose‐dependent manner | Class III PI3-kinase may be a possible target for COVID-19 therapeutic development |
| Zhang et al. [332] | 2021 | In vitro/in vivo | Preparation of MAbs from female BALB/c mice and wild-type Balb/c mice were intranasally inoculated with hACE2-encoded adenovirus 5 (Ad5-hACE2) to allow expression of the hACE2 receptor in the lung, followed by intranasal infection with live SARS-CoV-2 3 days later | Mouse anti-SARS-CoV-2-neutralizing MAbs: 2H2 and 3C1 | Spike (S) protein | (IC50) of 12 ng/mL effectively treat SARS-CoV-2-infected mice even when administered as late as 24 h post-infection | |
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