key: cord-1015993-zvtuuxzc
authors: Vidoni, Chiara; Fuzimoto, Andréa; Ferraresi, Alessandra; Isidoro, Ciro
title: Targeting autophagy with natural products to prevent SARS-CoV-2 infection
date: 2021-10-14
journal: J Tradit Complement Med
DOI: 10.1016/j.jtcme.2021.10.003
sha: d3bd295274b246ea0daac419c60df521c160f2dd
doc_id: 1015993
cord_uid: zvtuuxzc

Autophagy is a catabolic process that maintains internal homeostasis and energy balance through the lysosomal degradation of redundant or damaged cellular components. During virus infection, autophagy is triggered both in parenchymal and in immune cells with different finalistic objectives: in parenchymal cells, the goal is to destroy the virion particle while in macrophages and dendritic cells the goal is to expose virion-derived fragments for priming the lymphocytes and initiate the immune response. However, some viruses have developed a strategy to subvert the autophagy machinery to escape the destructive destiny and instead exploit it for virion assembly and exocytosis. Coronaviruses (like SARS-CoV-2) possess such ability. The autophagy process requires a set of proteins that constitute the core machinery and is controlled by several signaling pathways. Here, we report on natural products capable of interfering with SARS-CoV-2 cellular infection and replication through their action on autophagy. The present study provides support to the use of such natural products as adjuvant therapeutics for the management of COVID-19 pandemic to prevent the virus infection and replication, and so mitigating the progression of the disease.

In December 2019, rose in Wuhan (Hubei Province, China) what would soon become one of the most contagious viral pandemics in recent human history 1 Although vaccination constitutes an important and useful means for preventing the spread of the disease, it remains urgent to identify effective strategies to treat at the earliest stages those who get infected. A variety of protocols for treating COVID-19 patients have been proposed, which include antiviral drugs, monoclonal antibodies, antibiotics, and anti-inflammatory drugs in combination and sequential administration depending on the disease stage and the clinical condition of the patient. Natural products provide a source of bioactive molecules that can be exploited for novel and effective treatments to prevent the fatal evolution of this disease 2-6 .

These natural biomolecules could interfere at any stage of the virus life cycle, from entering the cell to its replication, assembly, and exit from the cell, as well as by triggering virus clearance 3, 7-10 . Autophagy, a vesicular-driven degradation pathway of cellular components, is triggered as a cellular stress response to viral infection, and it is involved in all steps of CoV replication and propagation 11, 12 .

In this review, we will focus on those natural products that have been shown effective in preventing and limiting the infection and replication of CoV through the modulation of the autophagy process. First, we will introduce the principal cellular and molecular features of the autophagy process, then we will discuss how SARS-CoV-2 viral replication interacts with the autophagy-lysosomal vesicular traffic, and finally, we will present and discuss the mechanisms of action of the natural products that potentially interfere with these processes.

Autophagy (herein referring to macroautophagy) is a catabolic process that maintains cell homeostasis and preserves cell viability under pathological stresses, including viral infections 11, 13 . The two other known autophagy pathways, namely microautophagy and chaperone-J o u r n a l P r e -p r o o f mediated autophagy, play a little if any role in virus infections. Here, we will provide a glance at the autophagy machinery, as a comprehensive description of this process can be found elsewhere 14, 15 .

Autophagy starts with the formation of a double-membrane vesicle, named the autophagosome that sequesters the substrates to be delivered to the lysosome for full degradation. The core machinery includes more than 30 autophagy-related (ATG) proteins. The main steps and ATG proteins involved in the autophagy process are depicted in Figure 1 . In brief, the autophagosome starts to form from an 'omega-shaped' membrane (the phagophore) in the proximity of the endoplasmic reticulum-Golgi area. Two important events mark this step. First, the cytosolic protein LC3 normally associated with the microtubules (MAP-LC3) is sequentially processed by certain ATG proteins (including ATG4, ATG5, ATG7, and ATG12)

to be conjugated to phosphatidylethanolamine and thereafter be inserted into the bilayer of both the inner and outer membrane of the autophagosome. This vacuolar form of LC3 is known as isoform LC3-II. Second, while the autophagosome is under construction, the autophagy substrate (e.g., protein aggregates) to be degraded is bound by the p62/SQSTM1 protein and sequestered in the lumen. In the case of mitophagy, oxidized mitochondria are sequestered via interaction with BNIP3. The autophagosome will eventually fuse with endosomes and lysosomes to form the amphysome and autolysosome, respectively. The acidic pH and the hydrolytic enzymes (especially, cathepsins) ensure the complete digestion of the material within the autolysosome, from which the elementary substrates will be released in the cytoplasm for recycling.

J o u r n a l P r e -p r o o f The autophagy process is finely tuned by redundant pathways that sense the lack of nutrients and growth factors or energy sources as well as the presence of bacteria and viruses in the cytoplasm or endocytic organelles 16 . The main signaling pathways that control autophagy involve the PI3KC1-AKT-mTORC1 negative axis and the AMPK-mTORC1-ULK1 positive axis. The mTORC1 complex is the central hub receiving signals from amino acids, growth factors, and glucose, and controls negatively autophagy by inhibiting the ULK1 complex, whereas AMPK, triggered by the rise of AMP following ATP production impairment (as it occurs, for instance, when glucose is lacking), inhibits mTORC1 and activates ULKC1.

Downstream to ULKC1 is the Vps15-BECLIN1-PI3KC3-ATG14L complex, known as the "autophagy interactome", which starts the signal for the autophagosome formation.

The autophagy pathway described above is known as the "canonical" pathway, which is typically active at a basal rate in all eucaryotic cells for keeping the macromolecular J o u r n a l P r e -p r o o f on the membrane are specifically targeted by SARS-CoV-2 through the S protein 31 . Whichever the path used for entering the cell, the cleavage of the S protein into the subunits S1 and S2 by host proteases such as endosomal cathepsin L, furin, trypsin, transmembrane protease serine protease 2 (TMPRSS-2), or human airway trypsin-like protease is an obligated step for allowing the fusion between the viral envelope and host cell membranes (either endosomal or plasma membrane) and the release of the genome into the cytoplasm 31, 32 . Accordingly, inhibition of this proteolytic step greatly reduces the cellular viral load 28, 31 .

Once the viral genome is free in the cytoplasm, the translation at the endoplasmic reticulum starts with the synthesis of the pp1a and pp1ab that are subsequently processed to produce the nsps. The latter, and particularly nsps 3, 4, and 6, induce the formation of a double-membrane vesicle (DMV) from deranged membranes of the endoplasmic reticulum 33 . Also, the 3'terminal of the viral genome is translated to produce the S, E, M, N, and accessory proteins.

Meanwhile, the RNA genome is replicated. DMV is the platform where the virus assembles 28 .

It has been reported that CoV particles egress the cell via the conventional secretory pathway passing through the Golgi apparatus. Yet, it seems that β-CoV virions are preferentially de- with lysosomes, thus impairing autophagy clearance efficiency 10, 40, 41 . The combined effect is that autophagosomal membranes accumulate and could be retrieved for the generation of DMV, where the virus assembles 41, 42 . Further, it has been hypothesized that such an effect in antigen-presenting cells would compromise the capability of autophagosomes to deliver viral components to lysosomes for degradation as well as reducing antigen presentation and/or exposure to TLRs 41 . In line with this finding, it has been shown that membrane-associated papain-like protease PLP2 (PLP2-TM) of SARS-CoV interacts with BECLIN1 and promotes the accumulation of autophagosomes through impairment of autophagosome-lysosome fusion 43 . In the same line, MERS-CoV replication was associated with proteasomal degradation of BECLIN1 and impaired fusion of autophagosomes and lysosomes 44 . Inhibiting BECLIN1 degradation restored autophagy and drastically reduced MERS-CoV replication 44 , implying that stimulation of autophagy to completion could be a strategy for limiting the viral output.

The mechanistic interaction between CoV entry, replication, and exit processes with the endocytic, autophagy, and endosomal-lysosomal system is schematized in Figure 2 . 

The relationship between autophagy and viral infection also includes the participation of autophagy in innate and adaptive immunity and modulation of the inflammatory response 45 .

Autophagy plays a major role in viral antigen processing and priming of CD4+ and CD8+ Tlymphocytes that is instrumental for humoral and cellular response to virus infection 39, 46 .

Autophagy also dampens inflammation. Lack of ATG5 in dendritic cells resulted in increased secretion of proinflammatory cytokines upon respiratory syncytial virus infection 47 . Similarly, the lack of RUBICON, a BECLIN-1 interacting protein essential in the non-canonical autophagy pathway LAP, resulted in significant production of IL-6, IL-1β, and IL-12 upon viral infection 48 .

In the next paragraph, we present the natural products that have the potential to interfere with the autophagy-dependent infection and replication of the main human pathogenic viruses. We discuss their mechanism of action in light of similarities with SARS-CoV-2, and aim to provide additional supporting information for the development of new drugs for the management of the current pandemic.

Herbs and natural compounds interfere in different stages of the viral cycle and exert a supportive role on the host immune response for clearing viral infections 49 . For instance, berberine, baicalin, and resveratrol inhibited the human immunodeficiency virus (HIV), influenza A virus (IAV), human cytomegalovirus (HCMV), and many others through different pathways [49] [50] [51] [52] [53] [54] [55] . Here, we present a selection of herbs and phytocompounds that specifically explored autophagic mechanisms to counteract the infection and replication of RNA viruses such as enterovirus-71 (EV71), influenza viruses (H1N1, H3N2, H5N1, H9N2), and HCV.

Also, we extended our search by looking at the in silico evidence of each herb-compound for its possible activity toward SARS-CoV-2 infection (Tables 1 and 2 ).

Berberine (BBR) is an isoquinoline alkaloid present in several herbal species such as Coptidis rhizome, Phellodendron chinese, and Berberis vulgaris 56 Molecular docking and dynamics simulations revealed that BBR significantly interacts with SARS-CoV-2 3CL PRO , S protein, and ACE2 receptor [59] [60] [61] (Table 1 ). This suggests that BBR could prevent viral entry and fusion and interfere with the autophagy processes and the biogenesis of DMV by affecting the 3CL PRO -mediated generation of nsps 4-16 62 . Accordingly, BBR potently inhibited SARS-CoV-2 replication 63, 64 . Advantages of using BBR include the reported low cytotoxicity and high cellular viability, prevention of infection at low concentrations, no serious adverse effects, and easy penetration in various organ systems (e.g., liver, kidneys, muscles, and brain) 63, 65 . Disadvantages to its use include poor aqueous solubility and rapid metabolism. Yet, this issue can be resolved by using nanoparticles and lipid-based nanocarriers 65 .

Baicalin, a flavonoid extracted from Scutellaria baicalensis can hinder the formation of autophagosomes and inhibit the H3N2-induced autophagy by counteracting the mTOR suppression in the infected epithelial and macrophage cells 66 . Also, baicalin downregulated the expression of LC3-II, ATG5, and ATG12, and this led to a decreased virus replication 66 .

Baicalin may interact with the SARS-CoV-2 S and PL PRO , nsp4, and 3CL PRO proteins 3, 34, 67, 68 , suggesting another way to prevent the induction of autophagy. Notably, the in silico evidence indicates the potential of baicalein, baicalin, and some baicalin derivatives to block 3CL PRO 3, 34, 69, 70 , baicalin to counteract nsp4, nsp15, nsp16, RdRp, and furin 66, 67, 71 , and baicalein to inhibit nsp14 N and C terminals 72 . 75 . In vitro studies show that RV may be effective at suppressing CoVs including the SARS-CoV-2 with low cytotoxicity while maintaining cell viability even at high concentrations 76, 77 . In silico analysis demonstrated the ability of RV and its derivatives to strongly and stably block SARS-CoV-2 proteins PL PRO , RdRp, and S protein 78, 79 . RV could act as an ACE2 receptor inhibitor, preventing the formation of the S1/ACE2 complex and viral endocytosis, and DMV biogenesis. Furthermore, RV could impact the autophagic process through inhibition of PL PRO -mediated generation of nsps. These actions make RV an interesting candidate for the treatment of SARS-CoV-2 infection.

Catechins are major polyphenol compounds found in green tea leaves. There are five major This effect was associated with mTOR-mediated inhibition of autophagy 107 . On the contrary, PGG was active against IAV, limiting the expression of viral M2 and NP proteins through induction of autophagy 108 . In silico studies show that PGG can interact with SARS-CoV-2 3CL PRO and S/ACE2 complex 109, 110 (Supplementary Table 1 

analyses also demonstrated that PGG may hinder SARS-CoV-1 and SARS-CoV-2 109 .

Altogether, PGG could halt SARS-CoV-2 through impeding attachment and endocytosis, and through modulation of the autophagic pathway.

Aloe vera extract can suppress IAV (H1N1 and H3N2)-induced autophagy 111 (Table 1) .

However, Aloe vera and its isolates may inhibit other SARS-CoV-2 structural and nonstructural proteins that we are unaware of.

Evodiamine, the major active compound of Evodia rutaecarpa, was shown to inhibit IAV- 

Autophagy inhibition (EV71) ↓ p-PERK, P-eIF2, ATF4, GRP78, and CHOP ↓ LC3-II  ↓ LC3-II/LC3-I ratio  ↓ IL-6, IL 

Activation of RAB-5 > defects in lysosome biogenesis and increase lysosomal pH ↑ Lysosomal pH > induces TFEB nuclear translocation Inhibition of autophagosome-lysosome fusion ↑ LC3-II accumulation ↑ p62 

It is evident that we have a lot more information on natural products that inhibit rather than induce autophagy for contrasting RNA viral infections. Also, some herbs (e.g., berberine) could either promote or inhibit autophagy. It may appear confusing that the reported studies on the antiviral effect elicited by the natural products could be obtained either way, through induction or inhibition of autophagy. One first possible explanation resides in differences in the experimental models such as the type of RNA virus researched, i.e., its modality of entry in the cell, its replication and egress from the cell, and the genetic background of the cell (that determine how the autophagy stress response is regulated). Importantly, the RNA virus itself can induce autophagy or impair the autophagy flux depending on its stage of replication, i.e., the viral proteins being synthesized and processed. Besides, and most importantly, we have to consider the methodology employed to assess autophagy, which could lead to Although the SARS-CoV-2 mutations are happening much more slowly than HIV and influenza virus, researchers detected 12,706 mutations in its genome, the majority being single nucleotide polymorphisms (SNPs) (reviewed in 117 ). Viral mutations can be neutral, beneficial, or deleterious. So far, the majority of mutations in the SARS-CoV-2 genome are considered neutral, and most of them involve the nsp6, nsp11, nsp13, and S protein (reviewed in 117 ). The J o u r n a l P r e -p r o o f role of SARS-CoV-2 structural and non-structural protein mutations on the autophagic process is still uncertain 118 . As autophagy is a double-edged sword, it is unclear, for example, if nsp6 mutations would favor viral replication and evasion from the host immune response, or if it would counteract it 118 . However, the main mutation of the D614G variant is at the interface between the individual spike protomers, and not in the RBD of S protein 117, 119 . Therefore, the herbs and compounds seen to block the S protein RBD are still potentially useful to impede adhesion and halt virus-induced autophagy. As the mutations continue to happen, their interference in the autophagic machinery and the usefulness of herbs and compounds depend on our understanding of these same mutations.

The interaction between autophagy, either canonical and non-canonical, and virus infection is complex and may result in: (i) the virus is effectively degraded via autophagy (virophagy) or (ii) the virus de-regulates the process and uses the autophagy machinery for its replication and egression from the cell 120 . Several drugs targeting autophagy have been repurposed as possible therapeutics for COVID-19 12, 121 . Here, we reported the literature data on natural products that showed an effect on the autophagy process in RNA viral infections. Based on the similarity among RNA viruses, and the research of these herbs for SARS-CoV-2, we hypothesize that they may also work for SARS-CoV-2. Yet, extensive additional research is necessary to validate in vivo this hypothesis. In support of our hypothesis, we also associated, first hand, the results of the in silico research of herbs and natural compounds for SARS-CoV-2 and how intervention on the reported target proteins could hinder attachment, fusion, endocytosis, and DMV biogenesis and consequently inhibit virus-induced autophagy (Fig. 3 ).

J o u r n a l P r e -p r o o f Table 1 .

Thus, in silico research could provide important hints for research on target proteins and autophagic pathways for viral infections. In this line, a recent review uncovered the capacity of artemisinin derivatives to block SARS-CoV-2/host proteins such as artesunate (3CL PRO , E protein, helicase, N protein, and nsp3, 10, 14, and 15), artemisinin (3CL PRO , GRP78 receptor), artemether (N protein, helicase, nsp10, and nsp15), MOL736 (cathepsin-L), artelinic acid (S protein), arteannuin B (N protein), and artenimol/DHA (N protein) 122 . As the strongest inhibition were attained by artesunate and artemisinin, it gives us a hint that they may potentially impede DMV biogenesis and autophagy, and hinder viral replication pointing to potential future research. Interestingly, a recent in vitro study reported the suppression of SARS-CoV-2 and two of its variants (UK B1.1.7 and South Africa B1.351) by the A. annua hot water leaf extract 123 . In this study, artemisinin was not the main antiviral agent, while artesunate, artemether, and dihydroartemisinin were deemed ineffective or cytotoxic at elevated concentrations 123 . Likely, the viral inhibition was due to the combined components J o u r n a l P r e -p r o o f

Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet

Do nutrients and other bioactive molecules from foods have anything to say in the treatment against COVID-19? Environ Res

Natural products and their derivatives against coronavirus: A review of the non-clinical and pre-clinical data

Quercetin and Vitamin C: An Experimental, Synergistic Therapy for the Prevention and Treatment of SARS-CoV-2 Related Disease (COVID-19). Front Immunol

Natural products and phytochemicals as potential anti-SARS-CoV-2 drugs

Traditional Herbal Medicines, Bioactive Metabolites, and Plant Products Against COVID-19: Update on Clinical Trials and Mechanism of Actions

The antiviral and coronavirus-host protein pathways inhibiting properties of herbs and natural compounds -Additional weapons in the fight J o u r n a l P r e -p r o o f against the COVID-19 pandemic?

Screening of phytochemicals as potent inhibitor of 3-chymotrypsin and papain-like proteases of SARS-CoV2: an in silico approach to combat COVID-19

Molecular docking study of potential phytochemicals and their effects on the complex of SARS-CoV2 spike protein and human ACE2. Sci Rep

Cell Clearing Systems as Targets of Polyphenols in Viral Infections: Potential Implications for COVID-19 Pathogenesis. Antioxidants (Basel)

Coronavirus interactions with the cellular autophagy machinery

The role of autophagy in controlling SARS-CoV-2 infection: An overview on virophagy-mediated molecular drug targets

Selective autophagy and viruses

Autophagy: machinery and regulation. Microb Cell

Guidelines for the use and interpretation of assays for monitoring autophagy

So Many Roads: the Multifaceted Regulation of Autophagy Induction

Canonical and non-canonical autophagy: variations on a common theme of self-eating?

Non-canonical Autophagy: Facts and Prospects

Molecular regulation of autophagy machinery by mTORdependent and -independent pathways

A noncanonical MEK/ERK signaling pathway regulates autophagy via regulating Beclin 1

MAPK/JNK signalling: a potential autophagy regulation pathway

Toll-like receptor signalling in macrophages links the autophagy pathway to phagocytosis

A ravenous defense: canonical and non-canonical autophagy in immunity

Autophagy, EVs, and Infections: A Perfect Question for a Perfect Time

Non-canonical autophagy functions of ATG16L1 in epithelial cells limit lethal infection by influenza A virus

Coronaviruses: an overview of their replication and pathogenesis

Genomic characterization of the 2019 novel human-pathogenic coronavirus isolated from a patient with atypical pneumonia after visiting Wuhan. Emerg Microbes Infect

The SARS-Coronavirus Infection Cycle: A Survey of Viral Membrane Proteins, Their Functional Interactions and Pathogenesis

Coronavirus cell entry occurs through the endo-/lysosomal pathway in a proteolysis-dependent manner

Extracellular RNA Sensing by Pattern Recognition Receptors

Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV

Coronavirus membrane fusion mechanism offers a potential target for antiviral development

Severe acute respiratory syndrome coronavirus nonstructural proteins 3, 4, and 6 induce double-membrane vesicles. mBio

Altan-Bonnet N. β-Coronaviruses Use Lysosomes for Egress Instead of the Biosynthetic Secretory Pathway

Viruses and the autophagy pathway

Coronaviruses Hijack the LC3-I-positive EDEMosomes, ERderived vesicles exporting short-lived ERAD regulators, for replication. Cell Host Microbe

Canonical and Noncanonical Autophagy as Potential Targets for COVID-19. Cells

Virgin HW 4th. Coronavirus replication does not require the autophagy gene ATG5. Autophagy

Autophagy during viral infection -a double-edged sword

Coronavirus nsp6 proteins generate autophagosomes from the endoplasmic reticulum via an omegasome intermediate

Coronavirus NSP6 restricts autophagosome expansion

Subversion of cellular autophagosomal machinery by RNA viruses

Coronavirus membrane-associated papain-like proteases induce autophagy through interacting with Beclin1 to negatively regulate antiviral innate immunity

Rein T. SKP2 attenuates autophagy through Beclin1-ubiquitination and its inhibition reduces MERS

Coronavirus infection

Autophagy and the immune system

Autophagy proteins in antigen processing for presentation on MHC molecules

Autophagic protein ATG5 controls antiviral immunity via glycolytic reprogramming of dendritic cells against respiratory syncytial virus infection

The autophagy regulator Rubicon is a feedback inhibitor of CARD9-mediated host innate immunity

Antiviral activity of berberine

Antiviral activity of baicalin against influenza A (H1N1/H3N2) virus in cell culture and in mice and its inhibition of neuraminidase

Baicalin from Scutellaria baicalensis blocks respiratory syncytial virus (RSV) infection and reduces inflammatory cell infiltration and lung injury in mice

Deciphering the potential of baicalin as an antiviral agent for Chikungunya virus infection

Flavonoid baicalin inhibits HIV-1 infection at the level of viral entry

Baicalin, a metabolite of baicalein with antiviral activity against dengue virus

Antiviral Activity of Resveratrol against Human and Animal Viruses

Berberine: Botanical Occurrence, Traditional Uses, Extraction Methods, and Relevance in Cardiovascular, Metabolic, Hepatic, and Renal Disorders

Berberine suppresses influenza virus-triggered NLRP3 inflammasome activation in macrophages by inducing mitophagy and decreasing mitochondrial ROS

Synthesis and Evolution of Berberine Derivatives as a New Class of Antiviral Agents against Enterovirus 71 through the MEK/ERK Pathway and Autophagy. Molecules

Ethnomedicines of Indian origin for combating COVID-19 infection by hampering the viral replication: using structure-based drug discovery approach

In silico investigation of phytoconstituents from Indian medicinal herb 'Tinospora cordifolia (giloy)' against SARS-CoV-2 (COVID-19) by molecular dynamics approach

A small molecule compound berberine as an orally active therapeutic candidate against COVID-19 and SARS: A computational and mechanistic study

Double-Membrane Vesicles as Platforms for Viral Replication

Berberine and Obatoclax Inhibit SARS-Cov-2 Replication in Primary Human Nasal Epithelial Cells In Vitro

In vitro evaluation of antiviral activity of single and combined repurposable drugs against SARS-CoV-2

Natural Products Isolated from Oriental Medicinal Herbs Inactivate Zika Virus. Viruses

Baicalin inhibits autophagy induced by influenza A virus H3N2

In silico identification and validation of natural antiviral compounds as potential inhibitors of SARS-CoV-2 methyltransferase

Whole Genome Analysis and Targeted Drug Discovery Using Computational Methods and High Throughput Screening Tools for Emerged Novel Coronavirus (2019-nCoV)

Scutellaria baicalensis extract and baicalein inhibit replication of SARS-CoV-2 and its 3C-like protease in vitro

Flavonoids with inhibitory activity against SARS-CoV-2 3CLpro

In silico virtual screening, characterization, docking and molecular dynamics studies of crucial SARS-CoV-2 proteins

Potential treatment with Chinese and Western medicine targeting NSP14 of SARS-CoV-2

Resveratrol: a review of plant sources, synthesis, stability, modification and food application

Resveratrol-loaded nanoparticles inhibit enterovirus 71 replication through the oxidative stress-mediated ERS/autophagy pathway

Effective inhibition of MERS-CoV infection by resveratrol

Resveratrol Inhibits HCoV-229E and SARS-CoV-2 Coronavirus Replication In Vitro

Resveratrol inhibits the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in cultured Vero cells

Molecular modelling of the antiviral action of Resveratrol derivatives against the activity of two novel SARS CoV-2 and 2019-nCoV receptors

Stilbene-based natural compounds as promising drug candidates against COVID-19

A Review of the Antiviral Role of Green Tea Catechins. Molecules

Catechin inhibiting the H1N1 influenza virus associated with the regulation of autophagy

Identifying the natural polyphenol catechin as a multi-targeted agent against SARS-CoV-2 for the plausible therapy of COVID-19: an integrated computational approach. Brief Bioinform

Catechin and curcumin interact with S protein of SARS-CoV2 and ACE2 of human cell membrane: insights from computational studies. Sci Rep

Docking Characterization and in vitro Inhibitory Activity of Flavan-3-ols and Dimeric Proanthocyanidins Against the Main Protease Activity of SARS-Cov-2. Front Plant Sci

A molecular docking study of EGCG and theaflavin digallate with the druggable targets of SARS-CoV-2

Protease (Mpro) and Spike (S) Glycoprotein Inhibitors: A Molecular Docking Study

Black tea bioactives as inhibitors of multiple targets of SARS-CoV-2 (3CLpro, PLpro and RdRp): a virtual screening and molecular dynamic simulation study

Small molecule stabilization of non-native proteinprotein interactions of SARS-CoV-2 N protein as a mechanism of action against COVID-19

Biological Properties of Monomeric and Polymeric Catechins: Green Tea Catechins and Procyanidins

High-throughput screening for anti-influenza A virus drugs and study of the mechanism of procyanidin on influenza A virus-induced autophagy

Procyanidins and butanol extract of Cinnamomi Cortex inhibit SARS-CoV infection

The potential role of procyanidin as a therapeutic agent against SARS-CoV-2: a text mining, molecular docking and molecular dynamics simulation approach

Inhibition of angiotensin converting enzyme (ACE) activity by flavan-3-ols and procyanidins

Bioavailability of procyanidin dimers and trimers and matrix food effects in in vitro and in vivo models

Probing the impact of quercetin-7-O-glucoside on influenza virus replication influence

In silico screening of Chinese herbal medicines with the potential to directly inhibit 2019 novel coronavirus

Structural stability of SARS-CoV-2 3CLpro and identification of quercetin as an inhibitor by experimental screening

Targeting SARS-CoV-2 spike protein of COVID-19 with naturally occurring phytochemicals: an in silico study for drug development

In-silico screening of plant-derived antivirals against main protease, 3CLpro and endoribonuclease, NSP15 proteins of SARS-CoV-2

Perspectives on plant flavonoid quercetinbased drugs for novel SARS-CoV-2

Saikosaponin D suppresses enterovirus A71 infection by inhibiting autophagy

Antiviral effects of saikosaponins on human coronavirus 229E in vitro

An in-silico evaluation of different Saikosaponins for their potency against SARS-CoV-2 using NSP15 and fusion spike glycoprotein as targets

BhAVI-23'-A spice-herb based dietary infusion possessing in-vitro anti-viral potential

Essential Oils as Antiviral Agents. Potential of Essential Oils to Treat SARS-CoV-2 Infection: An In-Silico Investigation

Inhibition of Rabies Virus by 1,2,3,4,6-Penta-O-galloyl-β-d-Glucose Involves mTOR-Dependent Autophagy

Autophagy is involved in regulating influenza A virus RNA and protein synthesis associated with both modulation of Hsp90 induction and mTOR/p70S6K signaling pathway

The inhibitory effects of PGG and EGCG against the SARS-CoV-2 3C-like protease

1,2,3,4,6-Pentagalloyl Glucose, a RBD-ACE2 Binding Inhibitor to Prevent SARS-CoV-2 Infection

Aloe vera and its Components Inhibit Influenza A Virus-Induced Autophagy and Replication

Identification of potential inhibitors of SARS-CoV-2 main protease from Aloe vera compounds: A molecular docking study

A drug screening method based on the autophagy pathway and studies of the mechanism of evodiamine against influenza A virus

Biopharmacological considerations for accelerating drug development of deguelin, a rotenoid with potent chemotherapeutic and chemopreventive potential

Deguelin inhibits HCV replication through suppressing cellular autophagy via down regulation of Beclin1 expression in human hepatoma cells

Kurarinone Inhibits HCoV-OC43 Infection by Impairing the Virus-Induced Autophagic Flux in MRC-5 Human Lung Cells

Implications of the Novel Mutations in the SARS-CoV-2 Genome for

Transmission, Disease Severity, and the Vaccine Development

Evolutionary analysis of SARS-CoV-2: how mutation of Non-Structural Protein 6 (NSP6) could affect viral autophagy

Making Sense of Mutation: What D614G Means for the COVID-19 Pandemic Remains Unclear

Viruses and the autophagy pathway

Therapeutic Potential of Exploiting Autophagy Cascade Against Coronavirus Infection. Front Microbiol

An overview of the anti-SARS-CoV-2 properties of

Artemisia annua, its antiviral action, protein-associated mechanisms, and repurposing for COVID-19 treatment

Artemisia annua L. extracts inhibit the in vitro replication of SARS-CoV-2 and two of its variants