Solanaceae Family Phytochemicals as Inhibitors of 3C-Like Protease of SARS-CoV-2: An In Silico Analysis

COVID-19, caused by the coronavirus SARS-CoV-2, emerged in late December 2019 in Wuhan, China. As of 8 April 2022, the virus has caused a global pandemic, resulting in 494,587,638 infections leading to 6,170,283 deaths around the world. Although several vaccines have received emergency authorization from USA and UK drug authorities and two more in Russia and China, it is too early to comment on the prolonged effectiveness of the vaccines, their availability, and affordability for the developing countries of the world, and the daunting task to vaccinate 7 billion people of the world with two doses of the vaccine with additional booster doses. As a result, it is still worthwhile to search for drugs and several promising leads have been found, mainly through in silico studies. In this study, we have examined the binding energies of several alkaloids and anthocyanin derivatives from the Solanaceae family, a family which contains common consumable vegetables and fruit items such as eggplant, pepper, and tomatoes. Our study demonstrates that Solanaceae family alkaloids such as incanumine and solaradixine, as well as anthocyanins and anthocyanidins, have very high predicted binding energies for the 3C-like protease of SARS-CoV-2 (also known as Mpro). Since Mpro is vital for SARS-CoV-2 replication, the compounds merit potential for further antiviral research towards the objective of obtaining affordable drugs.     

Potential Use of Tea Tree Oil as a Disinfectant Agent against Coronaviruses: A Combined Experimental and Simulation Study

The COVID-19 pandemic has highlighted the relevance of proper disinfection procedures and renewed interest in developing novel disinfectant materials as a preventive strategy to limit SARS-CoV-2 contamination. Given its widely known antibacterial, antifungal, and antiviral properties, Melaleuca alternifolia essential oil, also named Tea tree oil (TTO), is recognized as a potential effective and safe natural disinfectant agent. In particular, the proposed antiviral activity of TTO involves the inhibition of viral entry and fusion, interfering with the structural dynamics of the membrane and with the protein envelope components. In this study, for the first time, we demonstrated the virucidal effects of TTO against the feline coronavirus (FCoVII) and the human coronavirus OC43 (HCoV-OC43), both used as surrogate models for SARS-CoV-2. Then, to atomistically uncover the possible effects exerted by TTO compounds on the outer surface of the SARS-CoV-2 virion, we performed Gaussian accelerated Molecular Dynamics simulations of a SARS-CoV-2 envelope portion, including a complete model of the Spike glycoprotein in the absence or presence of the three main TTO compounds (terpinen-4-ol, γ-terpinene, and 1,8-cineole). The obtained results allowed us to hypothesize the mechanism of action of TTO and its possible use as an anti-coronavirus disinfectant agent.     

Glycyrrhizic Acid Inhibits SARS-CoV-2 Infection by Blocking Spike Protein-Mediated Cell Attachment

Glycyrrhizic acid (GA), also known as glycyrrhizin, is a triterpene glycoside isolated from plants of Glycyrrhiza species (licorice). GA possesses a wide range of pharmacological and antiviral activities against enveloped viruses including severe acute respiratory syndrome (SARS) virus. Since the S protein (S) mediates SARS coronavirus 2 (SARS-CoV-2) cell attachment and cell entry, we assayed the GA effect on SARS-CoV-2 infection using an S protein-pseudotyped lentivirus (Lenti-S). GA treatment dose-dependently blocked Lenti-S infection. We showed that incubation of Lenti-S virus, but not the host cells with GA prior to the infection, reduced Lenti-S infection, indicating that GA targeted the virus for infection. Surface plasmon resonance measurement showed that GA interacted with a recombinant S protein and blocked S protein binding to host cells. Autodocking analysis revealed that the S protein has several GA-binding pockets including one at the interaction interface to the receptor angiotensin-converting enzyme 2 (ACE2) and another at the inner side of the receptor-binding domain (RBD) which might impact the close-to-open conformation change of the S protein required for ACE2 interaction. In addition to identifying GA antiviral activity against SARS-CoV-2, the study linked GA antiviral activity to its effect on virus cell binding.     

Naphthoquine: A Potent Broad-Spectrum Anti-Coronavirus Drug In Vitro

COVID-19 has spread around the world and caused serious public health and social problems. Although several vaccines have been authorized for emergency use, new effective antiviral drugs are still needed. Some repurposed drugs including Chloroquine, Hydroxychloroquine and Remdesivir were immediately used to treat COVID-19 after the pandemic. However, the therapeutic effects of these drugs have not been fully demonstrated in clinical studies. In this paper, we found an antimalarial drug, Naphthoquine, showed good broad-spectrum anti-coronavirus activity. Naphthoquineinhibited HCoV-229E, HCoV-OC43 and SARS-CoV-2 replication in vitro, with IC₅₀ = 2.05 ± 1.44 μM, 5.83 ± 0.74 μM, and 2.01 ± 0.38 µM, respectively. Time-of-addition assay was also performed to explore at which stage Naphthoquine functions during SARS-CoV-2 replication. The results suggested that Naphthoquine may influence virus entry and post-entry replication. Considering the safety of Naphthoquine was even better than that of Chloroquine, we think Naphthoquine has the potential to be used as a broad-spectrum drug for coronavirus infection.     

Marine Brominated Tyrosine Alkaloids as Promising Inhibitors of SARS-CoV-2

There have been more than 150 million confirmed cases of SARS-CoV-2 since the beginning of the pandemic in 2019. By June 2021, the mortality from such infections approached 3.9 million people. Despite the availability of a number of vaccines which provide protection against this virus, the evolution of new viral variants, inconsistent availability of the vaccine around the world, and vaccine hesitancy, in some countries, makes it unreasonable to rely on mass vaccination alone to combat this pandemic. Consequently, much effort is directed to identifying potential antiviral treatments. Marine brominated tyrosine alkaloids are recognized to have antiviral potential. We test here the antiviral capacity of fourteen marine brominated tyrosine alkaloids against five different target proteins from SARS-CoV-2, including main protease (M^pro) (PDB ID: 6lu7), spike glycoprotein (PDB ID: 6VYB), nucleocapsid phosphoprotein (PDB ID: 6VYO), membrane glycoprotein (PDB ID: 6M17), and non-structural protein 10 (nsp10) (PDB ID: 6W4H). These marine alkaloids, particularly the hexabrominated compound, fistularin-3, shows promising docking interactions with predicted binding affinities (S-score = −7.78, −7.65, −6.39, −6.28, −8.84 Kcal/mol) for the main protease (M^pro) (PDB ID: 6lu7), spike glycoprotein (PDB ID: 6VYB), nucleocapsid phosphoprotein (PDB ID: 6VYO), membrane glycoprotein (PDB ID: 6M17), and non-structural protein 10 (nsp10) (PDB ID: 6W4H), respectively, where it forms better interactions with the protein pockets than the native interaction. It also shows promising molecular dynamics, pharmacokinetics, and toxicity profiles. As such, further exploration of the antiviral properties of fistularin-3 against SARS-CoV-2 is merited.     

Structure-based virtual screening and molecular dynamics of phytochemicals derived from Saudi medicinal plants to identify potential COVID-19 therapeutics

Coronavirus disease 2019 (COVID-19) has affected almost every country in the world by causing a global pandemic with a high mortality rate. Lack of an effective vaccine and/or antiviral drugs against SARS-CoV-2, the causative agent, has severely hampered the response to this novel coronavirus. Natural products have long been used in traditional medicines to treat various diseases, and purified phytochemicals from medicinal plants provide a valuable scaffold for the discovery of new drug leads. In the present study, we performed a computational screening of an in-house database composed of ~1000 phytochemicals derived from traditional Saudi medicinal plants with recognised antiviral activity. Structure-based virtual screening was carried out against three druggable SARS-CoV-2 targets, viral RNA-dependent RNA polymerase (RdRp), 3-chymotrypsin-like cysteine protease (3CL^pro) and papain like protease (PL^pro) to identify putative inhibitors that could facilitate the development of potential anti-COVID-19 drug candidates. Computational analyses identified three compounds inhibiting each target, with binding affinity scores ranging from −9.9 to −6.5 kcal/mol. Among these, luteolin 7-rutinoside, chrysophanol 8-(6-galloylglucoside) and kaempferol 7-(6″-galloylglucoside) bound efficiently to RdRp, while chrysophanol 8-(6-galloylglucoside), 3,4,5-tri-O-galloylquinic acid and mulberrofuran G interacted strongly with 3CL^pro, and withanolide A, isocodonocarpine and calonysterone bound tightly to PL^pro. These potential drug candidates will be subjected to further in vitro and in vivo studies and may assist the development of effective anti-COVID-19 drugs.     

In silico exploration of binding potentials of anti SARS-CoV-1 phytochemicals against main protease of SARS-CoV-2

The phytochemicals can play complementary medicine compared to synthetic drugs considering their natural origin, safety, and low cost. Phytochemicals hold a key position for the expansion of drug development against corona viruses and need better consideration to the agents that have already been shown to display effective activity against various strains of corona viruses. In this study, we performed molecular docking studies on potential forty seven phytochemicals which are SARS-CoV-1 M^pro inhibitors to identify potential candidate against the main proteins of SARS-CoV-2. In Silico Molecular docking studies revealed that phytochemicals 16 (Broussoflavan A), 22 (Dieckol), 31 (Hygromycin B), 45 (Sinigrin) and 46 (Theaflavin-3,3′-digallate) exhibited excellent SARS-CoV-2 M^pro inhibitors. Furthermore, supported by Molecular dynamics (MD) simulation analysis such as Root Mean Square Deviation (RMSD), Root Mean Square Fluctuation (RMSF), Radius of gyration (Rg) and H-bond interaction analysis. We expect that our findings will provide designing principles for new corona virus strains and establish important frameworks for the future development of antiviral drugs.     

Antiviral Efficacy of Selected Natural Phytochemicals against SARS-CoV-2 Spike Glycoprotein Using Structure-Based Drug Designing

SARS-CoV-2 is a highly virulent coronavirus that first surfaced in late 2019 and has since created a pandemic of the acute respiratory sickness known as “coronavirus disease 2019” (COVID-19), posing a threat to human health and public safety. S-RBD is a coronaviral protein that is essential for a coronavirus (CoV) to bind and penetrate into host cells. As a result, it has become a popular pharmacological target. The goal of this study was to find potential candidates for anti-coronavirus disease 2019 (COVID-19) drugs by targeting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) S-RBD with novel bioactive compounds and molecular interaction studies of 15,000 phytochemicals belonging to different flavonoid subgroups. A spike protein crystal structure attached to the ACE2 structure was obtained from the PDB database. A library of 15,000 phytochemicals was made by collecting compounds from different databases, such as the Zinc-database, PubChem-database, and MPD3-database. This library was docked against a receptor binding domain of a spike glycoprotein through the Molecular Operating Environment (MOE). The top drug candidates Phylloflavan, Milk thistle, Ilexin B and Isosilybin B, after virtual screening, were selected on the basis of the least binding score. Phylloflavan ranked as the top compound because of its least binding affinity score of −14.09 kcal/mol. In silico studies showed that all those compounds showed good activity and could be used as an immunological response with no bioavailability issues. Absorption, distribution, metabolism, excretion and a toxicological analysis were conducted through SwissADME. Stability and effectiveness of the docked complexes were elucidated by performing the 100 ns molecular dynamic simulation through the Desmond package.     

Plant-Derived Antiviral Compounds as Potential Entry Inhibitors against Spike Protein of SARS-CoV-2 Wild-Type and Delta Variant: An Integrative in SilicoApproach

The wild-type SARS-CoV-2 has continuously evolved into several variants with increased transmissibility and virulence. The Delta variant which was initially identified in India created a devastating impact throughout the country during the second wave. While the efficacy of the existing vaccines against the latest SARS-CoV-2 variants remains unclear, extensive research is being carried out to develop potential antiviral drugs through approaches like in silico screening and drug-repurposing. This study aimed to conduct the docking-based virtual screening of 50 potential phytochemical compounds against a Spike glycoprotein of the wild-type and the Delta SARS-CoV-2 variant. Subsequently, molecular docking was performed for the five best compounds, such as Lupeol, Betulin, Hypericin, Corilagin, and Geraniin, along with synthetic controls. From the results obtained, it was evident that Lupeol exhibited a remarkable binding affinity towards the wild-type Spike protein (−8.54 kcal/mol), while Betulin showed significant binding interactions with the mutated Spike protein (−8.83 kcal/mol), respectively. The binding energy values of the selected plant compounds were slightly higher than that of the controls. Key hydrogen bonding and hydrophobic interactions of the resulting complexes were visualized, which explained their greater binding affinity against the target proteins—the Delta S protein of SARS-CoV-2, in particular. The lower RMSD, the RMSF values of the complexes and the ligands, Rg, H-bonds, and the binding free energies of the complexes together revealed the stability of the complexes and significant binding affinities of the ligands towards the target proteins. Our study suggests that Lupeol and Betulin could be considered as potential ligands for SARS-CoV-2 spike antagonists. Further experimental validations might provide new insights for the possible antiviral therapeutic interventions of the identified lead compounds and their analogs against COVID-19 infection.     

Potential Antiviral Action of Alkaloids

Viral infections and outbreaks have become a major concern and are one of the main causes of morbidity and mortality worldwide. The development of successful antiviral therapeutics and vaccines remains a daunting challenge. The discovery of novel antiviral agents is a public health emergency, and extraordinary efforts are underway globally to identify safe and effective treatments for different viral diseases. Alkaloids are natural phytochemicals known for their biological activities, many of which have been intensively studied for their broad-spectrum of antiviral activities against different DNA and RNA viruses. The purpose of this review was to summarize the evidence supporting the efficacy of the antiviral activity of plant alkaloids at half-maximum effective concentration (EC₅₀) or half-maximum inhibitory concentration (IC₅₀) below 10 μM and describe the molecular sites most often targeted by natural alkaloids acting against different virus families. This review highlights that considering the devastating effects of virus pandemics on humans, plants, and animals, the development of high efficiency and low-toxicity antiviral drugs targeting these viruses need to be developed. Furthermore, it summarizes the current research status of alkaloids as the source of antiviral drug development, their structural characteristics, and antiviral targets. Overall, the influence of alkaloids at the molecular level suggests a high degree of specificity which means they could serve as potent and safe antiviral agents waiting for evaluation and exploitation.     

Computational Analysis Reveals Monomethylated Triazolopyrimidine as a Novel Inhibitor of SARS-CoV-2 RNA-Dependent RNA Polymerase (RdRp)

The human population is still facing appalling conditions due to several outbreaks of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) virus. The absence of specific drugs, appropriate vaccines for mutants, and knowledge of potential therapeutic agents makes this situation more difficult. Several 1, 2, 4-triazolo [1, 5-a] pyrimidine (TP)-derivative compounds were comprehensively studied for antiviral activities against RNA polymerase of HIV, HCV, and influenza viruses, and showed immense pharmacological interest. Therefore, TP-derivative compounds can be repurposed against the RNA-dependent RNA polymerase (RdRp) protein of SARS-CoV-2. In this study, a meta-analysis was performed to ensure the genomic variability and stability of the SARS-CoV-2 RdRp protein. The molecular docking of natural and synthetic TP compounds to RdRp and molecular dynamic (MD) simulations were performed to analyse the dynamic behaviour of TP compounds at the active site of the RdRp protein. TP compounds were also docked against other non-structural proteins (NSP1, NSP2, NSP3, NSP5, NSP8, NSP13, and NSP15) of SARS-CoV-2. Furthermore, the inhibition potential of TP compounds was compared with Remdesivir and Favipiravir drugs as a positive control. Additionally, TP compounds were analysed for inhibitory activity against SARS-CoV RdRp protein. This study demonstrates that TP analogues (monomethylated triazolopyrimidine and essramycin) represent potential lead molecules for designing an effective inhibitor to control viral replication. Furthermore, in vitro and in vivo studies will strengthen the use of these inhibitors as suitable drug candidates against SARS-CoV-2.     

Antiviral Activity of Metabolites from Peruvian Plants against SARS-CoV-2: An In Silico Approach

(1) Background: The COVID-19 pandemic lacks treatments; for this reason, the search for potential compounds against therapeutic targets is still necessary. Bioinformatics tools have allowed the rapid in silico screening of possible new metabolite candidates from natural resources or repurposing known ones. Thus, in this work, we aimed to select phytochemical candidates from Peruvian plants with antiviral potential against three therapeutical targets of SARS-CoV-2. (2) Methods: We applied in silico technics, such as virtual screening, molecular docking, molecular dynamics simulation, and MM/GBSA estimation. (3) Results: Rutin, a compound present in Peruvian native plants, showed affinity against three targets of SARS-CoV-2. The molecular dynamics simulation demonstrated the high stability of receptor–ligand systems during the time of the simulation. Our results showed that the Mpro-Rutin system exhibited higher binding free energy than PLpro-Rutin and N-Rutin systems through MM/GBSA analysis. (4) Conclusions: Our study provides insight on natural metabolites from Peruvian plants with therapeutical potential. We found Rutin as a potential candidate with multiple pharmacological properties against SARS-CoV-2.     

Nanoemulsions: The rising star of antiviral therapeutics and nanodelivery system—current status and prospects

Nanoemulsions (NEs) of essential oil (EO) have significant potential to target microorganisms, especially viruses. They act as a vehicle for delivering antiviral drugs and vaccines. Narrowing of drug discovery pipeline and the emergence of new viral diseases, especially, coronavirus disease, have created a niche to use NEs for augmenting currently available therapeutic options. Published literature demonstrated that EOs have an inherent broad spectrum of activity across bacterial, fungal, and viral pathogens. The emulsification process significantly improved the efficacy of the active ingredients in the EOs. This article highlights the research findings and patent developments in the last 2 years especially, in EO antiviral activity, antiviral drug delivery, vaccine delivery, viral resistance development, and repurposing EO compounds against SARS-CoV-2.     

Antiviral Activities of Halogenated Emodin Derivatives against Human Coronavirus NL63

The current COVID-19 outbreak has highlighted the need for the development of new vaccines and drugs to combat Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2). Recently, various drugs have been proposed as potentially effective against COVID-19, such as remdesivir, infliximab and imatinib. Natural plants have been used as an alternative source of drugs for thousands of years, and some of them are effective for the treatment of various viral diseases. Emodin (1,3,8-trihydroxy-6-methylanthracene-9,10-dione) is a biologically active anthraquinone with antiviral activity that is found in various plants. We studied the selectivity of electrophilic aromatic substitution reactions on an emodin core (halogenation, nitration and sulfonation), which resulted in a library of emodin derivatives. The main aim of this work was to carry out an initial evaluation of the potential to improve the activity of emodin against human coronavirus NL63 (HCoV-NL63) and also to generate a set of initial SAR guidelines. We have prepared emodin derivatives which displayed significant anti-HCoV-NL63 activity. We observed that halogenation of emodin can improve its antiviral activity. The most active compound in this study was the iodinated emodin analogue E_3I, whose anti-HCoV-NL63 activity was comparable to that of remdesivir. Evaluation of the emodin analogues also revealed some unwanted toxicity to Vero cells. Since new synthetic routes are now available that allow modification of the emodin structure, it is reasonable to expect that analogues with significantly improved anti-HCoV-NL63 activity and lowered toxicity may thus be generated.     

Virtual screening of approved drugs as potential SARS-CoV-2 main protease inhibitors

The global emergency caused by COVID-19 makes the discovery of drugs capable of inhibiting SARS-CoV-2 a priority, to reduce the mortality and morbidity of this disease. Repurposing approved drugs can provide therapeutic alternatives that promise rapid and ample coverage because they have a documented safety record, as well as infrastructure for large-scale production. The main protease of SARS-CoV-2 (Mpro) is an excellent therapeutic target because it is critical for viral replication; however, Mpro has a highly flexible active site that must be considered when performing computer-assisted drug discovery. In this work, potential inhibitors of the main protease (Mpro) of SARS-Cov-2 were identified through a docking-assisted virtual screening procedure. A total of 4384 drugs, all approved for human use, were screened against three conformers of Mpro. The ligands were further studied through molecular dynamics simulations and binding free energy analysis. A total of nine currently approved molecules are proposed as potential inhibitors of SARS-CoV-2. These molecules can be further tested to speed the development of therapeutics against COVID-19.     

Gold Metallodrugs to Target Coronavirus Proteins: Inhibitory Effects on the Spike-ACE2 Interaction and on PLpro Protease Activity by Auranofin and Gold Organometallics**

Gold complexes have a long tradition in medicine and for many examples antirheumatic, anticancer or anti-infective effects have been confirmed. Herein, we evaluated the lead compound Auranofin and five selected gold organometallics as inhibitors of two relevant drug targets of severe acute respiratory syndrome coronaviruses (SARS-CoV). The gold metallodrugs were effective inhibitors of the interaction of the SARS-CoV-2 spike protein with the angiotensin converting enzyme 2 (ACE2) host receptor and might thus interfere with the viral entry process. The gold metallodrugs were also efficient inhibitors of the papain-like protease (PLpro) of SARS-CoV-1 and SARS-CoV-2, which is a key enzyme in the viral replication. Regarding PLpro from SARS-CoV-2, the here reported inhibitors are among the very first experimentally confirmed examples with activity against this target enzyme. Importantly, the activity of the complexes against both PLpro enzymes correlated with the ability of the inhibitors to remove zinc ions from the labile zinc center of the enzyme. Taken together, the results of this pilot study suggest further evaluation of gold complexes as SARS-CoV antiviral drugs.     

Fruit Bromelain-Derived Peptide Potentially Restrains the Attachment of SARS-CoV-2 Variants to hACE2: A Pharmacoinformatics Approach

Before entering the cell, the SARS-CoV-2 spike glycoprotein receptor-binding domain (RBD) binds to the human angiotensin-converting enzyme 2 (hACE2) receptor. Hence, this RBD is a critical target for the development of antiviral agents. Recent studies have discovered that SARS-CoV-2 variants with mutations in the RBD have spread globally. The purpose of this in silico study was to determine the potential of a fruit bromelain-derived peptide. DYGAVNEVK. to inhibit the entry of various SARS-CoV-2 variants into human cells by targeting the hACE binding site within the RBD. Molecular docking analysis revealed that DYGAVNEVK interacts with several critical RBD binding residues responsible for the adhesion of the RBD to hACE2. Moreover, 100 ns MD simulations revealed stable interactions between DYGAVNEVK and RBD variants derived from the trajectory of root-mean-square deviation (RMSD), radius of gyration (Rg), and root-mean-square fluctuation (RMSF) analysis, as well as free binding energy calculations. Overall, our computational results indicate that DYGAVNEVK warrants further investigation as a candidate for preventing SARS-CoV-2 due to its interaction with the RBD of SARS-CoV-2 variants.     

Targeting non-structural proteins and 3CLpro in SARS-CoV-2 virus using phytochemicals from medicinal plants - In-silico approach

In the present study, the main protease 3CL^pro and non-structural protein (NSP-12 with co-factors 7 and 8) trimer complex are used to study the protein-drug interactions with the phytochemicals from Ocimum Sanctum, Tinospora Cordifolia, Glycyrrhiza Glabra, and Azadirachta Indica. Which can give insight to be used as potent antiviral drugs against SARS-CoV-2. Twenty phytochemicals, five from each plant species, known for their wide range of biological activities were chosen from the literature. The in-silico study was carried out using virtual screening tools and the top five, which showed the least binding energies, were selected. Molecular docking tools revealed that gedunin and epoxy azadiradione proved to be excellent inhibitors for 3CL^pro and so did Tinosporide for non-structural-protein complex. Further, the best-hit phytochemicals with respect to structure similarities with FDA drugs and investigatory drugs, were considered for comparative study. Molecular docking was done to check the drug-protein interactions and to check the inhibitory responses of these drugs against the viral protein. The analyses showed that the phytochemicals had similar responses on the protein complex but with exceptionally higher inhibitory responses hence which may be taken for further clinical study.     

Reviving chloroquine for anti-SARS-CoV-2 treatment with cucurbit[7]uril-based supramolecular formulation

The wide-spreading SARS-CoV-2 virus has put the world into boiling water for more than a year, however pharmacological therapies to act effectively against coronavirus disease 2019 (COVID-19) remain elusive. Chloroquine (CQ), an antimalarial drug, was found to exhibit promising antiviral activity in vitro and in vivo at a high dosage, thus CQ was approved by the FDA for the emergency use authorization (EUA) in the fight against COVID-19 in the US, but later was revoked the EUA status due to the severe clinical toxicity. Herein, we show that supramolecular formulation of CQ by a macrocyclic host, curcurbit[7]uril (CB[7]), reduced its non-specific toxicity and improved its antiviral activity against coronavirus, working in synergy with CB[7]. CB[7] was found to form 1:1 host-guest complexes with CQ, with a binding constant of ∼10⁴ L/mol. The CQ-CB[7] formulation decreased the cytotoxicity of CQ against Vero E6 and L-02 cell lines. In particular, the cytotoxicity of CQ (60 μmol/L) against both Vero E6 cell line and L-02 cell lines was completely inhibited in the presence of 300 μmol/L and 600 μmol/L CB[7], respectively. Furthermore, the CB[7] alone showed astonishing antiviral activity in SARS-CoV-2 infected Vero E6 cells and mouse hepatitis virus strain A59 (MHV-A59) infected N2A cells, and synergistically improved the antiviral activity of CQ-CB[7], suggesting that CB[7]-based CQ formulation has a great potential as a safe and effective antiviral agent against SARS-CoV-2 and other coronavirus.