Glycyrrhiza glabra, liquorice, glycyrrhizic acid for COVID-19

The outbreak of SARS-CoV-2 developed into a global pandemic affecting millions of people worldwide. Despite one year of intensive research, the current treatment options for SARS-CoV-2 infected people are still limited. Clearly, novel antiviral compounds for the treatment of SARS-CoV-2 infected patients are still urgently needed. Complementary medicine is used along with standard medical treatment and accessible to a vast majority of people worldwide. Natural products with antiviral activity may contribute to improve the overall condition of SARS-CoV-2 infected individuals. In the present study, we investigated the antiviral activity of glycyrrhizin, the primary active ingredient of the licorice root, against SARS-CoV-2. We demonstrated that glycyrrhizin potently inhibits SARS-CoV-2 replication in vitro. Furthermore, we uncovered the underlying mechanism and showed that glycyrrhizin blocks the viral replication by inhibiting the viral main protease Mpro that is essential for viral replication. Our data indicate that the consumption of glycyrrhizin-containing products such as licorice root tea of black licorice may be of great benefit for SARS-CoV-2 infected people. Furthermore, glycyrrhizin is a good candidate for further investigation for clinical use to treat COVID-19 patients.

The phytotherapeutic properties of Glycyrrhiza glabra (licorice) extract are mainly attributed to glycyrrhizin (GR) and glycyrrhetinic acid (GA). Among their possible pharmacological actions, the ability to act against viruses belonging to different families, including SARS coronavirus, is particularly important. With the COVID-19 emergency and the urgent need for compounds to counteract the pandemic, the antiviral properties of GR and GA, as pure substances or as components of licorice extract, attracted attention in the last year and supported the launch of two clinical trials. In silico docking studies reported that GR and GA may directly interact with the key players in viral internalization and replication such as angiotensin-converting enzyme 2 (ACE2), spike protein, the host transmembrane serine protease 2, and 3-chymotrypsin-like cysteine protease. In vitro data indicated that GR can interfere with virus entry by directly interacting with ACE2 and spike, with a nonspecific effect on cell and viral membranes. Additional anti-inflammatory and antioxidant effects of GR cannot be excluded. These multiple activities of GR and licorice extract are critically re-assessed in this review, and their possible role against the spread of the SARS-CoV-2 and the features of COVID-19 disease is discussed.

The outbreak of SARS-CoV-2 developed into a global pandemic affecting millions of people worldwide. Despite one year of intensive research, the current treatment options for SARS-CoV-2 infected people are still limited. Clearly, novel antiviral compounds for the treatment of SARS-CoV-2 infected patients are still urgently needed. Complementary medicine is used along with standard medical treatment and accessible to a vast majority of people worldwide. Natural products with antiviral activity may contribute to improve the overall condition of SARS-CoV-2 infected individuals. In the present study, we investigated the antiviral activity of glycyrrhizin, the primary active ingredient of the licorice root, against SARS-CoV-2. We demonstrated that glycyrrhizin potently inhibits SARS-CoV-2 replication in vitro. Furthermore, we uncovered the underlying mechanism and showed that glycyrrhizin blocks the viral replication by inhibiting the viral main protease Mpro that is essential for viral replication. Our data indicate that the consumption of glycyrrhizin-containing products such as licorice root tea of black licorice may be of great benefit for SARS-CoV-2 infected people. Furthermore, glycyrrhizin is a good candidate for further investigation for clinical use to treat COVID-19 patients.

Abstract Objectives We investigate the effects of Licorice (Glycyrrhiza glabra L.) root extract, an anti-inflammatory natural medicine, compared to the usual therapeutic regimen on clinical symptoms and laboratory signs in patients with confirmed COVID-19 that are moderately ill. Trial design This is a single-center, open-label, randomized, clinical trial with parallel-group design. This study is being conducted at Shahid Mohammadi Hospital, Bandar Abbas, Iran. Participants Both male and female patients with ≥18 years of age (≥ 35 kg of weight), admitted at the Shahid Mohammadi Hospital, Hormozgan University of Medical Sciences, Bandar Abbas for treatment, screened for the following criteria. Inclusion criteria: 1. Confirmed diagnosis of SARS-CoV-2 infection (via polymerase chain reaction [PCR] and/or antibody test). 2. Presenting as moderate COVID-19 pneumonia (via chest computed tomography (CT) and/or X-ray) requiring hospitalization. 3. Hospitalized ≤48 hours. 4. Signing informed consent and willingness of study participant to accept randomization to any assigned treatment arm. Exclusion criteria: 1. Underlying diseases, including chronic heart disease, chronic hypertension, severe renal failure, severe liver failure, and thyroid disorders. 2. Severe and critical COVID-19 pneumonia. 3. Use of warfarin, selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), diuretics, corticosteroids, and antiarrhythmic drugs. 4. Treatment with Investigational and antiviral therapy in a clinical study within one month before randomization. 5. History of allergy to Licorice. 6. Pregnancy and breastfeeding. Intervention and comparator Intervention group: The standard treatment regimen for COVID-19 along with a Licorice-based herbal preparation (D-Reglis ®, Irandarouk Pharmaceutical Company, Iran) at a dose of 760 mg three times a day for a period of seven days. Control group: The standard treatment for COVID-19 based on the Iranian Ministry of Health and Medical Education's protocol for a period of seven days. Main outcomes The recovery rate of clinical symptoms, including fever, dry cough, and tiredness, as well as paraclinical features, including thrombocytopenia, lymphocytopenia, and C-reactive protein, are evaluated as primary outcomes within seven days of randomization. Time to improvement of clinical and paraclinical features and length of stay in a hospital, along with the incidence of adverse reactions are also evaluated as the secondary outcomes within seven days of randomization. Randomization An electronic table of random numbers will be used to allocate the included participants into either control or intervention groups (in a 1:1 ratio) using the simple randomization method. Blinding (masking) This is an open-label trial without blinding and placebo control. Numbers to be randomized (sample size) A total of 60 participants randomizes (30 patients allocated to the intervention group and 30 patients allocated to..

Aim: Today, the COVID-19 pandemic, which causes deaths in 224 countries around the world, continues to show its effect all over the world. However, unfortunately, there are few studies that determine the effect of natural products derived from plants on COVID-19. However, as it is known, the source of most drugs is plants and medicinal aromatic plants have been used frequently for therapeutic purposes since the existence of humanity. The aim of this study is to investigate the cytotoxic effects of six medicinal plants such as Licorice (Glycyrrhiza glabra), Saffron (Crocus sativus L.), Black Cumin (Nigella sativa L.), Laurel (Lauris nobilis), Buckwheat (Lavandula stoechas) and Zahter (Thymbra spicata L. var. spicata) and their antiviral activities against SARS-CoV-2 in vitro conditions.
 Material and Method: This study was carried out in two stages. In the first stage, plants were collected and extracts were obtained. At the beginning of the second stage, cytotoxic effects on vero cells at non-cytotoxic broad-spectrum concentrations against SARS-CoV-2 in cell culture of six medicinal plants were investigated. In this step, the concentration of six ethnobotanically important medicinal plants that were not cytotoxic to SARS-CoV-2 was determined. In the continuation of the second stage, the plants were evaluated for the determination of viral replication inhibition and their antiviral effectiveness against SARS-CoV-2. In this step, in vitro antiviral effects of plants against SARS-CoV-2 were determined at a concentration that did not show cytotoxic effects.. 
 Results: The concentration of six plants used in the study without cytotoxic effects was determined.. Among the plants examined, it was determined that the only plant that was effective against SARS-CoV-2 in vitro conditions was the licorice plant (Glycyrrhiza glabra). The licorice plant was found to inhibit SARS-CoV-2 in vitro at the 2nd dilution (1:4) after the initial concentration.
 Conclusion: According to the findings obtained from our study, it was determined that the licorice plant was effective against the SARS-CoV-2 in vitro conditions. Supported by further studies, it can be thought that our findings may contribute to the fight against the COVID-19 pandemic.
 Keywords: SARS-CoV-2, Antiviral Efficacy, Plant Extract, Licorice (Glycyrrhiza glabra), Saffron (Crocus sativus L.), Black Cumin (Nigella sativa L.), Laurel (Lauris nobilis), Buckwheat (Lavandula stoechas), Zahter (Thymbra spicata L. var. spicata).

Background: Coronavirus disease 2019 (COVID-19) is now a worldwide public health crisis. The causative pathogen is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Novel therapeutic agents are desperately needed. Because of the frequent mutations in the virus and its ability to cause cytokine storms, targeting the viral proteins has some drawbacks. Targeting cellular factors or pivotal inflammatory pathways triggered by SARS-CoV-2 may produce a broader range of therapies. Glycyrrhizic acid (GA) might be beneficial against SARS-CoV-2 because of its anti-inflammatory and antiviral characteristics and possible ability to regulate crucial host factors. However, the mechanism underlying how GA regulates host factors remains to be determined.Methods: In our report, we conducted a bioinformatics analysis to identify possible GA targets, biological functions, protein-protein interactions, transcription-factor-gene interactions, transcription-factor-miRNA coregulatory networks, and the signaling pathways of GA against COVID-19.Results: Protein-protein interactions and network analysis showed that ICAM1, MMP9, TLR2, and SOCS3 had higher degree values, which may be key targets of GA for COVID-19. GO analysis indicated that the response to reactive oxygen species was significantly enriched. Pathway enrichment analysis showed that the IL-17, IL-6, TNF-α, IFN signals, complement system, and growth factor receptor signaling are the main pathways. The interactions of TF genes and miRNA with common targets and the activity of TFs were also recognized.Conclusions: GA may inhibit COVID-19 through its anti-oxidant, anti-viral, and anti-inflammatory effects, and its ability to activate the immune system, and targeted therapy for those pathways is a predominant strategy to inhibit the cytokine storms triggered by SARS-CoV-2 infection.

Even though vaccination has started against COVID-19, people should continue maintaining personal and social caution as it takes months or years to get everyone vaccinated, and we are not sure how long the vaccine remains efficacious. In order to contribute to the mitigation of COVID-19 symptoms, the pharmaceutical industry aims to develop antiviral drugs to inhibit the SARS-CoV-2 replication and produce anti-inflammatory medications that will inhibit the acute respiratory distress syndrome (ARDS), which is the primary cause of mortality among the COVID-19 patients. In reference to these tasks, this article considers the properties of a medicinal plant named licorice (Glycyrrhiza glabra), whose phytochemicals have shown both antiviral and anti-inflammatory tendencies through previous studies. All the literature was selected through extensive search in various databases such as google scholar, Scopus, the Web of Science, and PubMed. In addition to the antiviral and anti-inflammatory properties, one of the licorice components has an autophagy-enhancing mechanism that studies have suggested to be necessary for COVID-19 treatment. Based on reviewing relevant professional and historical literature regarding the medicinal properties of licorice, it is suggested that it may be worthwhile to conduct in vitro and in vivo studies, including clinical trials with glycyrrhizic and glycyrrhetinic acids together with other flavonoids found in licorice, as there is the potentiality to provide natural interventions against COVID-19 symptoms.

ABSTRACT Objective: There is no definitive pharmacological strategy for COVID-19; thus, medicinal herbs can be an appropriate option for COVID-19 management. We investigated the efficacy of a D-reglis® tablet (root extract of licorice) as adjuvant therapy in critically ill patients with COVID-19 at intensive care units (ICUs) of Alzahra Teaching Hospital affiliated with Isfahan University of Medical Sciences, Isfahan, Iran. Methods: In the present double-blind, randomized, placebo-controlled clinical trial, critically ill cases with COVID-19 (n = 52) received a D-reglis® tablet (760 mg) or a placebo tablet for 5 days. The ICU stay length was the primary outcome. The secondary outcome included the changes in oxygen saturation, duration of mechanical ventilation, mortality rate, and Sequential Organ Failure Assessment (SOFA) Score during the study period. Findings: The ICU stay was significantly lower in the licorice group than in the placebo group (P = 0.015). No significant difference was detected between the groups regarding oxygen saturation, SOFA score, duration of mechanical ventilation, and mortality rate. Conclusion: The licorice tablet (D-reglis®) as an adjuvant treatment showed promising results regarding the ICU stay length in critically ill COVID-19 patients. However, further clinical trials with larger sample sizes, further duration of intervention, measurement of inflammatory markers, and further study about the molecular mechanism of the effect of licorice on COVID-19 should be done to obtain more conclusive findings.

There is currently no particular cure for coronavirus disease-19 (COVID-19). However, studies suggest that certain medicinal plants, fruits, and vegetables possess bioactive substances capable of ameliorating the disease. This review aims to articulate fruits, vegetables, and medicinal plants that have anti-coronavirus properties. Relevant articles were collected from reputable academic repositories, namely SpringerLink, PubMed, Google Scholar, and Scopus. Available information shows that alkaline-rich fruits and vegetables, such as mango, cabbage, lemon, onion, okra, carrot, cucumber, pepper, spinach, and avocado, have anti-coronavirus properties. The mentioned fruits and vegetables stimulate an unfavorable pH for the replication of the virus and normalize the acid-base imbalance induced in the lungs and kidneys of the infected. Fruits and vegetables also contain health-boosting substances such as proteins, amino acids, glycosides, vitamins, and minerals. Medicinal plants, including Clitoria ternatea L., Vitex trifolia L., Sphaeranthus indicus L., Clerodendrum inerme L. Gaertn., Glycyrrhiza glabra L., Strobilanthes cusia (Nees) Kuntze, Vitis vinifera var. aestivalis (Michx.) Kuntze, Hyoscyamus niger L., and Cedrela Sinensis Juss., also possess anti-coronavirus properties. Clitoria ternatea and Cedrela sinensis reduce the virus’s replication by shredding its receptor, called the angiotensin-converting enzyme 2 (ACE2). Vitex trifolia and Sphaeranthus indicus prevent hyper-inflammatory responses and cytokine storms. Glycyrrhiza glabra induces nitrous oxide synthase and blocks the virus’s replication. Clerodendrum inerme and Strobilanthes cusia inhibit the virus’s ribosome and protein translation. Vitis vinifera represses nucleocapsid protein and lowers apoptosis. Hyoscyamus niger inhibits Ca2+ channels and lessens breathing difficulties induced by the coronavirus. Thus, dietary supplements and drugs formulated with these medicinal plants, fruits, and vegetables may lessen the effects of COVID-19.

Desde o início da pandemia do novo coronavírus, houve grande preocupação diante de uma doença cujos possíveis impactos e morbidade ainda eram desconhecidos, iniciando, assim, uma corrida na descoberta de um tratamento para esta doença. Nesse sentido diversas pesquisas foram e estão sendo realizadas em busca de espécies vegetais passíveis de serem utilizadas na terapêutica da COVID-19. Portanto, esse estudo tem como objetivo realizar revisão de estudos etnodirigidos de espécies vegetais referenciadas na terapêutica e/ou prevenção da COVID-19. Foi realizada uma busca nas bases Scielo, LILACS e PubMed entre 2020 a 2022. Foram selecionados 32 artigos, predominando os de língua inglesa (n= 30), em 2021 (56,25%) e nos países Irã, Índia e Estados Unidos (15,62%); 86 espécies vegetais foram referidas, pertencentes a 51 famílias, com predomínio de Asteraceae e Laminaceae. As espécies mais referidas foram Glycyrrhiza glabra L. (4,65%) e Nigella sativa L. (3,48%), predominando o uso da raiz (29,4 %), preparadas como extrato aquoso (23,5%). Para futuros trabalhos, deve ser estimulada a continuidade dos estudos de validação com tais espécies, fundamentados na certificação de eficácia, segurança e qualidade; afim de minimizar os riscos do uso popular de produto inadequado e contribuir na pesquisa e desenvolvimento de um futuro bioproduto no tratamento do SARS-CoV-2.

Outbreaks of emerging infectious diseases continue to challenge human health. Novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has triggered a global coronavirus pandemic, namely COVID-19. Multiple variants of SARS-CoV-2 virus are circulating and raises question with respect to effectiveness of different lines of treatment such as vaccines and antiviral drugs. To find appropriate prevention/treatment, 21 plant-based ingredients were identified with antiviral properties. We pseudo typed SARS-CoV-2 on a lentiviral vector plasmid and tested the impact of five different herbal formulations in mammalian HEK293T cells. Viral inactivation assay showed that the natural extracts in herb-derived phytoconstituents based formulation, BITS-003 comprising of Bacopa monnieri, Glycyerrhiza glabra, Asparagus racemosus-wild, and Nigella sativa bear strong virucidal properties, inactivating enveloped viruses from 2log10 (or 99%) to >4log10 (or 99.99%). Moreover, bacterial and yeast cells treated with BITS-003 displayed reduced growth. Topical use of formulation as mouthwash/gargle will be effective in reducing symptoms of respiratory viral infections with a potential to decrease viral load in buccal/oral cavity. This may inhibit the coronavirus spreading to the lungs of infected person and at the same time will reduce the risk of viral transmission to other susceptible persons through micro-droplets originating from the oral cavity of the infected person.

The emergence of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has affected many countries throughout the world. As urgency is a necessity, most efforts have focused on identifying small molecule drugs that can be repurposed for use as anti-SARS-CoV-2 agents. Although several drug candidates have been identified using in silico method and in vitro studies, most of these drugs require the support of in vivo data before they can be considered for clinical trials. Several drugs are considered promising therapeutic agents for COVID-19. In addition to the direct-acting antiviral drugs, supportive therapies including traditional Chinese medicine, immunotherapies, immunomodulators, and nutritional therapy could contribute a major role in treating COVID-19 patients. Some of these drugs have already been included in the treatment guidelines, recommendations, and standard operating procedures. In this article, we comprehensively review the approved and potential therapeutic drugs, immune cells-based therapies, immunomodulatory agents/drugs, herbs and plant metabolites, nutritional and dietary for COVID-19.

Abstract Background The recent outbreak of the Coronavirus pandemic resulted in a successful vaccination program launched by the World Health Organization. However, a large population is still unvaccinated, leading to the emergence of mutated strains like alpha, beta, delta, and B.1.1.529 (Omicron). Recent reports from the World Health Organization raised concerns about the Omicron variant, which emerged in South Africa during a surge in COVID-19 cases in November 2021. Vaccines are not proven completely effective or safe against Omicron, leading to clinical trials for combating infection by the mutated virus. The absence of suitable pharmaceuticals has led scientists and clinicians to search for alternative and supplementary therapies, including dietary patterns, to reduce the effect of mutated strains. Main body This review analyzed Coronavirus aetiology, epidemiology, and natural products for combating Omicron. Although the literature search did not include keywords related to in silico or computational research, in silico investigations were emphasized in this study. Molecular docking was implemented to compare the interaction between natural products and Chloroquine with the ACE2 receptor protein amino acid residues of Omicron. The global Omicron infection proceeding SARS-CoV-2 vaccination was also elucidated. The docking results suggest that DGCG may bind to the ACE2 receptor three times more effectively than standard chloroquine. Conclusion The emergence of the Omicron variant has highlighted the need for alternative therapies to reduce the impact of mutated strains. The current review suggests that natural products such as DGCG may be effective in binding to the ACE2 receptor and combating the Omicron variant, however, further research is required to validate the results of this study and explore the potential of natural products to mitigate COVID-19. Graphical abstract

COVID-19 patients can exhibit a wide range of clinical manifestations affecting various organs and systems. Neurological symptoms have been reported in COVID-19 patients, both during the acute phase of the illness and in cases of long-term COVID. Moderate symptoms include ageusia, anosmia, altered mental status, and cognitive impairment, and in more severe cases can manifest as ischemic cerebrovascular disease and encephalitis. In this narrative review, we delve into the reported neurological symptoms associated with COVID-19, as well as the underlying mechanisms contributing to them. These mechanisms include direct damage to neurons, inflammation, oxidative stress, and protein misfolding. We further investigate the potential of small molecules from natural products to offer neuroprotection in models of neurodegenerative diseases. Through our analysis, we discovered that flavonoids, alkaloids, terpenoids, and other natural compounds exhibit neuroprotective effects by modulating signaling pathways known to be impacted by COVID-19. Some of these compounds also directly target SARS-CoV-2 viral replication. Therefore, molecules of natural origin show promise as potential agents to prevent or mitigate nervous system damage in COVID-19 patients. Further research and the evaluation of different stages of the disease are warranted to explore their potential benefits.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an enveloped respiratory β coronavirus that causes coronavirus disease (COVID-19), leading to a deadly pandemic that has claimed millions of lives worldwide. Like other coronaviruses, the SARS-CoV-2 genome also codes for non-structural proteins (NSPs). These NSPs are found within open reading frame 1a (ORF1a) and open reading frame 1ab (ORF1ab) of the SARS-CoV-2 genome and encode NSP1 to NSP11 and NSP12 to NSP16, respectively. This study aimed to collect the available literature regarding NSP inhibitors. In addition, we searched the natural product database looking for similar structures. The results showed that similar structures could be tested as potential inhibitors of the NSPs.

Abstract Serious illnesses caused by viruses are becoming the world’s most critical public health issues and lead millions of deaths each year in the world. Thousands of studies confirmed that the plant-derived medicines could play positive therapeutic effects on the patients with viral diseases. Since thousands of antiviral phytochemicals have been identified as lifesaving drugs in medical research, a comprehensive database is highly desirable to integrate the medicinal plants with their different medicinal properties. Therefore, we provided a friendly antiviral phytochemical database AVPCD covering 2537 antiviral phytochemicals from 383 medicinal compounds and 319 different families with annotation of their scientific, family and common names, along with the parts used, disease information, active compounds, links of relevant articles for COVID-19, cancer, HIV and malaria. Furthermore, each compound in AVPCD was annotated with its 2D and 3D structure, molecular formula, molecular weight, isomeric SMILES, InChI, InChI Key and IUPAC name and 21 other properties. Each compound was annotated with more than 20 properties. Specifically, a scoring method was designed to measure the confidence of each phytochemical for the viral diseases. In addition, we constructed a user-friendly platform with several powerful modules for searching and browsing the details of all phytochemicals. We believe this database will facilitate global researchers, drug developers and health practitioners in obtaining useful information against viral diseases.

The ongoing COVID-19 pandemic highlights the urgent need for effective antiviral agents and vaccines. Drug repositioning, which involves modifying existing drugs, offers a promising approach for expediting the development of novel therapeutics. In this study, we developed a new drug, MDB-MDB-601a-NM, by modifying the existing drug nafamostat (NM) with the incorporation of glycyrrhizic acid (GA). We assessed the pharmacokinetic profiles of MDB-601a-NM and nafamostat in Sprague-Dawley rats, revealing rapid clearance of nafamostat and sustained drug concentration of MDB-601a-NM after subcutaneous administration. Single-dose toxicity studies showed potential toxicity and persistent swelling at the injection site with high-dose administration of MDB-601a-NM. Furthermore, we evaluated the efficacy of MDB-601a-NM in protecting against SARS-CoV-2 infection using the K18 hACE-2 transgenic mouse model. Mice treated with 60 mg/kg and 100 mg/kg of MDB-601a-NM exhibited improved protectivity in terms of weight loss and survival rates compared to the nafamostat-treated group. Histopathological analysis revealed dose-dependent improvements in histopathological changes and enhanced inhibitory efficacy in MDB-601a-NM-treated groups. Notably, no viral replication was detected in the brain tissue when mice were treated with 60 mg/kg and 100 mg/kg of MDB-601a-NM. Our developed MDB-601a-NM, a modified Nafamostat with glycyrrhizic acid, shows improved protectivity against SARS-CoV-2 infection. Its sustained drug concentration after subcutaneous administration and dose-dependent improvements makes it a promising therapeutic option.

Abstract SARS-CoV-2, a newly discovered coronavirus, has been linked to the COVID-19 pandemic and is currently an important public health issue. Despite all the work done to date around the world, there is still no viable treatment for COVID-19. This study examined the most recent evidence on the efficacy and safety of several therapeutic options available including natural substances, synthetic drugs and vaccines in the treatment of COVID-19. Various natural compounds such as sarsapogenin, lycorine, biscoclaurine, vitamin B12, glycyrrhizic acid, riboflavin, resveratrol and kaempferol, various vaccines and drugs such as AZD1222, mRNA-1273, BNT162b2, Sputnik V, and remdesivir, lopinavir, favipiravir, darunavir, oseltamivir, and umifenovir, resp., have been discussed comprehensively. We attempted to provide exhaustive information regarding the various prospective therapeutic approaches available in order to assist researchers and physicians in treating COVID-19 patients.

Background. Since the beginning of the novel coronavirus (SARS-CoV-2) disease outbreak, there has been an increasing interest in discovering potential therapeutic agents for this disease. In this regard, we conducted a systematic review through an overview of drug development (in silico, in vitro, and in vivo) for treating COVID-19. Methods. A systematic search was carried out in major databases including PubMed, Web of Science, Scopus, EMBASE, and Google Scholar from December 2019 to March 2021. A combination of the following terms was used: coronavirus, COVID-19, SARS-CoV-2, drug design, drug development, In silico, In vitro, and In vivo. A narrative synthesis was performed as a qualitative method for the data synthesis of each outcome measure. Results. A total of 2168 articles were identified through searching databases. Finally, 315 studies (266 in silico, 34 in vitro, and 15 in vivo) were included. In studies with in silico approach, 98 article study repurposed drug and 91 studies evaluated herbal medicine on COVID-19. Among 260 drugs repurposed by the computational method, the best results were observed with saquinavir (n = 9), ritonavir (n = 8), and lopinavir (n = 6). Main protease (n = 154) following spike glycoprotein (n = 62) and other nonstructural protein of virus (n = 45) was among the most studied targets. Doxycycline, chlorpromazine, azithromycin, heparin, bepridil, and glycyrrhizic acid showed both in silico and in vitro inhibitory effects against SARS-CoV-2. Conclusion. The preclinical studies of novel drug design for COVID-19 focused on main protease and spike glycoprotein as targets for antiviral development. From evaluated structures, saquinavir, ritonavir, eucalyptus, Tinospora cordifolia, aloe, green tea, curcumin, pyrazole, and triazole derivatives in in silico studies and doxycycline, chlorpromazine, and heparin from in vitro and human monoclonal antibodies from in vivo studies showed promised results regarding efficacy. It seems that due to the nature of COVID-19 disease, finding some drugs with multitarget antiviral actions and anti-inflammatory potential is valuable and some herbal medicines have this potential.