The outbreak of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) has led to coronavirus disease-19 (COVID-19); a pandemic disease that has resulted in devastating social, economic, morbidity and mortality burdens. SARS-CoV-2 infects cells following receptor-mediated endocytosis and priming by cellular proteases. Following uptake, SARS-CoV-2 replicates in autophagosome-like structures in the cytosol following its escape from endolysosomes. Accordingly, the greater endolysosome pathway including autophagosomes and the mTOR sensor may be targets for therapeutic interventions against SARS-CoV-2 infection and COVID-19 pathogenesis. Naturally existing compounds (phytochemicals) through their actions on endolysosomes and mTOR signaling pathways might provide therapeutic relief against COVID-19. Here, we discuss evidence that some natural compounds through actions on the greater endolysosome system can inhibit SARS-CoV-2 infectivity and thereby might be repurposed for use against COVID-19.
SARS-CoV-2, COVID-19, Endolysosomes, Autophagy, Natural compounds
Severe acute respiratory syndrome coronavirus-2 (SARSCoV- 2) is an enveloped virus containing single-stranded RNA genomic material [1,2]. Coronavirus infectious disease-2019 (COVID-19) is a pandemic disease in humans caused by SARS-CoV-2 infection; symptoms and consequences include cardiovascular disorders, acute respiratory distress syndrome (ARDS), and death [3-5]. SARS-CoV-2 infects cells by viral spike proteins interacting with host cells expressing angiotensinconverting enzyme 2 (ACE2) receptors; the virus enters host cells following transmembrane protease serine 2 (TMPRSS2)-mediated priming [6-8]. To infect cells, the virus must be endocytosed into and then released from endolysosomes; a feature common to enveloped viruses [9,10]. In so doing, coronaviruses hijack the endocytic machinery such that they deliver their genomic material at replication sites without initiating host immune detection and host-pathogen responses [8,11-14]. Once released from endolysosomes into the cytosol, coronaviruses replicate in double membrane vesicles that resemble autophagosomes [15-18] and when viral levels are sufficiently high pathological conditions develop including cytokine storms [19-22]. Because endolysosomes are acidic organelles that contain ~60 acid hydrolases capable of catalyzing the degradation of viral particles, enhancing endolysosome acidification might suppress SARS-CoV-2 infection [15,23,24]. The acidic nature of lysosomes regulates the functions of endolysosomes and the autophagy system and multiple endolysosome-associated ion channels and proteins regulate lysosome acidity including vacuolar- ATPase, TRPML1, BK , SLC38A9 [26-29], and mammalian target of rapamycin (mTOR) [30-34].
mTOR downstream signaling pathways regulate fundamental cellular processes such as protein synthesis, metabolism, transcription, cell cycle, apoptosis, endolysosomes, autophagy, and immune regulation and tolerance [35-39]. Aberrant mTOR signaling is involved in various pathological conditions such as cancer and inflammation as well as cardiovascular and metabolic disorders [40,41]. In addition, multiple viruses can hijack the mTOR signaling system for the purpose of completing viral replication including influenza  and HIV-1 [43,44] as well as the coronaviruses MERS-CoV [45, 46] and SARS-CoV-2 [15, 47, 48].
The mTOR signaling pathway can be targeted to block the infection and replication of viruses other than coronaviruses by inducing autophagy and inhibiting viral protein synthesis [15,45-47,49,50]. Hence, mTOR might be targeted to suppress SARS-CoV-2 infection and COVID-19 using synthetic and natural compounds [51-57]. Natural compounds (phytochemicals) can enhance endolysosome acidification and autophagy by inhibiting mTOR-signaling pathways [49,58-64]. It has been suggested that increased consumption of phytochemicals or foods rich in phytochemicals might decrease the prevalence and severity of cancer, osteoporosis, and cardiovascular diseases . Fruits, legumes, vegetables, and cereals contain high levels of phytochemicals including carotenoids, terpenoids, phytosterols, flavonoids, isoflavones, isothiocyanates, and fibers; substances shown to have anti-inflammatory, anti-oxidant and anti-infectious properties . Phytochemicals can also enhance the degradative properties of endolysosomes and thereby suppress microbial infections as well as human metabolic and aging-related diseases [15,63,64]. Here, we briefly discuss natural compounds that affect endolysosomes and autophagy, the mTOR sensor, and as such, might find therapeutic use against SARS-CoV-2 infection and the pathogenesis of COVID-19.
Spermidine and spermine
Polyamines are generated endogenously from arginine and ornithine, and they are ingested as components of various plants [65,66]. Endogenously, putrescine synthesis from ornithine is catalyzed by ornithine decarboxylase [67-69] and from ornithine, the polyamines spermidine and spermine are generated . Exogenously, ingestion of polyamines protected against age-related memory loss [70,71] and rescued memory performance [71,72]. The cardio-protective , anti-inflammatory, and antioxidant [74-76], actions of the polyamine spermidine may be mediated by the induction of autophagy [71,77]. Moreover, spermidine and spermine induce 5’-AMP-activated protein kinase (AMPK) and inhibit the mTOR signaling pathway to induce autophagy and suppress functions of inflammatory dendritic cells [78-80]. Spermidine and spermine both inhibited SARS-CoV-2 infection and appeared to do so by inducing viral degradation in endolysosomes .
Resveratrol is a polyphenol with antioxidant and antiinflammatory properties, and resveratrol has been found to protect against oxidative damage in high-risk conditions like cancer, diabetes, heart diseases, neurodegenerative diseases, and microbial infections . Resveratrol is enriched in peanuts, berries, and red grapes [81,82], and it can be ingested in capsules containing Polygonum cuspidatum plant extracts [83,84]. Resveratrol has an ability to enhance autophagy and kill cancer cells by suppressing the phosphoinositide 3-kinase (PI3K)/A serine/threonine protein kinase (Akt)/mTOR signaling pathway and enhancing AMPK and sirtuin (SIRT1) pathways [85-88]. Resveratrol can exert antiviral effects against various viral infections  including herpes simplex virus , enterovirus 71, Epstein-Barr virus, respiratory syncytial virus, influenza, and Middle East Respiratory Syndrome-coronavirus (MERS-CoV) ; MERS-CoV is a family member of SARS-CoV-2 virus [91,92]. Co-administration of resveratrol with copper may be useful in suppressing SARS-CoV-2 replication and diminishing SARS-CoV-2-induced cytokine storms [93,94].
Phytoestrogens are natural compounds found in plants such as tofu, flaxseed, soybean, sesame seeds, and garlic [95,96]. Phytoestrogens exert estrogen-like effects  and have antioxidant, anti-inflammatory [97-100] and neuroprotective [101,102] properties as well as the ability to induce autophagy . Phytoestrogens restrict PI3K/ Akt/mTOR signaling pathways and this mechanism has been implicated in their ability to induce autophagy and kill cancer cells [104-106]. One estrogen, 17β-estradiol, is known already to suppress multiple viral infections including influenza , rubella , HIV-1 , HSV-1 , SARS-CoV , and SARS-CoV-2 [112-114].
Trehalose, also known as tremalose and mycose, is a stable disaccharide assembled from two molecules of d-glucose . Some plants, fungi, bacteria, and invertebrate animals can produce trehalose and use it as an energy source as well as to survive freezing and lack of water [116-118]. Trehalose has antioxidant  and neuroprotective properties [119-122], and it has been shown to inhibit HIV- 1 and mycobacterium tuberculosis (Mtb) co-infection by inducing the endolysosomal degradation pathway . Further, trehalose induced mTOR-independent autophagy and suppressed cytomegalovirus infection in different cell types .
Baicalin, a component of Scutellaria baicalensis and Scutellaria lateriflora , can protect against amyloid-β protein-, hydrogen peroxide [H2O2]-, middle cerebral artery occlusion-, and oxygen/glucose deprivationinduced neurotoxicity [126-131]. At least some of these protective effects might be mediated through its actions on endolysosomes because baicalin can attenuate high-fat diet-induced endolysosome deacidification . Baicalin can also induce apoptosis in cancer cells by downregulating mTOR signaling pathways [133-135]. The anti-influenza  effects of baicalin suggests its possible use against SARS-CoV-2 by targeting its 3CL protease enzyme .
Turmeric is a spice with many purported medicinal properties  and is a rich source of curcumin [139,140]. Curcumin (1,7-bis (4-hydroxy-3-methoxyphenyl)-1,6- heptadiene-3,5-dione) is also known as diferuloylmethane; a natural polyphenol present in the rhizome of turmeric (Curcuma longa) [140,141]. Curcumin has antioxidative and anti-inflammatory properties, and it has been used against arthritis, bacterial infections, metabolic syndrome, anxiety, and hyperlipidemia [142-147]. Curcumin has antiviral effects against a broad spectrum of viruses including herpes simplex virus-2 (HSV-2) , HIV-1, zikavirus , influenza virus , hepatitis virus , and human papillomavirus (HPV) . Moreover, curcumin increases endolysosomal functions by promoting lysosomal acidification and suppressing the mTOR sensor [152-154].
Quercetin is a flavonoid that is present in many plants and foods including onions, red wine, berries, green tea, apples, ginkgo biloba, and buckwheat . Quercetin has a broad range of biological activities including being anti-inflammatory, attenuating lipid peroxidation, inhibiting platelet aggregation [156-159], inducing cell death in cancer cells by enhancing autophagic flux and lysosomal activity , and suppressing PI3K/Akt/ mTOR signaling pathways [161-163]. Quercetin displays a broad range of antiviral properties; it interferes with virus entry, replication, and assembly [164-167]. Quercetin can suppress SARS-CoV-2 infection but has yet to be tested against COVID-19 .
Coumarin is a phenolic substance that is a fusion of benzene and α-pyrone rings [169,170]. Coumarin is present in Tonka bean (D. odorata) and Cinnamomum aromaticum and has also been isolated from various plants . Coumarins have anti-oxidant, anti-bacterial, anti-fungal, anti-viral, and anti-cancer properties [172-175]. A hybrid of phenylsulfonylfuroxan and coumarin induced caspase-dependent cell death, autophagy, and suppressed PI3K/Akt/mTOR signaling pathway to kill cancer cells [176-178]. Accordingly, it has been suggested that coumarin might protect against COVID-19 by blocking the protease enzyme of SARS-CoV-2 [179,180].
Epigallocatechin 3-gallate (EGCG)
EGCG is a component of tea leaves . EGCG has antioxidant properties and may prevent autoimmune diseases and cytokine storms [182-186] by blocking downstream inflammatory signaling pathways of the transcription factors STAT (signal transducer and activator of transcription 1/3) and NF-κB (nuclear factor kappa-lightchain- enhancer of activated B cells) [187-190]. EGCG upregulates AMPK activity in a dose-dependent manner and suppresses mTOR signaling in hepatoma cells . A computer-based study has shown that EGCG is an ATP-competitive inhibitor of Akt/mTOR and enhances autophagy by AMPK activation [192-194]. Moreover, EGCG synergistically enhanced curcumin’s effects on cancer cells by inducing autophagy through suppression of the Akt/mTOR signaling pathway .
Naringenin is a flavorless flavanone; a predominant flavanone in various herbs and fruits including grapefruits, citrus, and tomatoes [196-198]. Naringenin has hepatoprotective, anti-inflammatory, anti-mutagenic, anti-cancer, and anti-microbial [199-204] effects and may control neurological, metabolic, rheumatological, and cardiovascular diseases [205-207]. Moreover, naringenin is an inhibitor of endolysosome two-pore channels (TPCs) [208-210]; channels involved in SARS-CoV-2 and Ebola virus infections [211-213] as well as the ability of HIV-1 protein Tat to escape endolysosomes . Naringenin can induce cancer cell death by promoting autophagy and downregulate the Akt/mTOR signaling pathway [215-219]. These finding suggest a possible use of naringenin against COVID-19 by targeting TPCs and the Akt/mTOR signaling pathway [220-222].
The COVID-19 pandemic is a global disaster with devasting social, behavioral, economic and health ramifications. Endolysosomes play important roles in regulating SARSCoV- 2 infection and thus might be targeted therapeutically against COVID-19.
|Endolysosomes and autophagy||Anti-inflammatory||Anti-SARS-CoV-2 activity [References]||Scoring|
|Spermidine and spermine||Negatively regulates mTOR signaling pathway [15,78,79]||Autophagy inducer ||Potential anti-
|Restricts SARS-CoV-2 infec- tion by SKP2 modulation (in vitro) ||++|
|Resveratrol||Negatively regulates mTOR signaling
|Autophagy inducer [86,230,231]||Potential anti-
|MERS-CoV inhibition in vitro  SARS-CoV-2 inhibition in vitro [93,94] Proposed for clinical trials (NCT04542993)||+++|
|Phytoestro-gen||Negatively regulates mTOR signaling pathways [104-
|Autophagy inducer [103,104]||Potential anti- inflammatory [97,98,100,233]||Restricts SARS-CoV in vivo
 Suggested as a suppressor of COVID-19 [112,114,224,234-
236] Estrogen therapy (NCT04539626)
|Trehalose||No effect on
|Induces autophagy and lysosomal biogenesis by TFEB activation [120,122] Induces lysosomes
acidification and autophagy by mucolipin-1 (TRPML1)
activation to protect mycobacterium tuberculosis infection 
|Potential target against COVID-19 ||++|
|Baicalin||Negatively regulates mTOR signaling pathways [133-
|Autophagy inducer  Induces lysosomes acidification by promoting assembly of v-ATPase pump ||Potential anti-
|Suppresses COVID-19 patho- logical condition in vivo, in vitro [137,242-244] Proposed for clinical trial (NCT03830684)||+++|
|Curcumin||Negatively regulates mTOR signaling pathways [152-
|Autophagy inducer [59,60]||Potential anti- inflammatory [142,143,245]||Proposed against COVID-19 [245-248] Proposed for clinical trial against COVID-19 (NCT04353310)||+++|
|Quercetin||Negatively regulates mTOR signaling pathways [161,162]||Autophagy inducer [160,161]||Potential anti- inflammatory [156,249]||Potential target against COVID-19 [168,250-253] Proposed for clinical trial against COVID-19 (NCT04377789)||+++|
|Coumarin||Negatively regulates mTOR signaling pathways ||Autophagy inducer [176,178]||Potential anti-
|Potential target against COVID-19 (in silico) 179,180]||++|
|Epigallocat-echin 3-gal- late [EGCG]||Negatively regulates mTOR signaling pathways [192,194,195]||Autophagy inducer [194,255]||Potential anti- inflammatory [183,185,187,189]||Potential target against COVID-19 and Proposed as previfenon (NCT04446065) [186,256-258]||+++|
|Naringenin||Negatively regu- lates mTOR sig- naling pathways ||Autophagy inducer [217,219,259] A blocker of Two pore channels (TPCs). TPCs are highly involved in SARS-CoV-2’s entry into cells ||Potential anti- inflammatory [200,261,262]||Suppresses SARS-
CoV-2 infection in vitro [221,222,263]
Table 1: Potential natural compounds against SARS-CoV-2 infection and COVID-19 pathogenesis (Scoring according to evidence; +++ (high confidence), ++ (moderate confidence).
Relevant to COVID-19, endolysosomes are important regulators of innate immune responses and antigen presentation and phytochemicals have purported antiinflammatory, anti-oxidant, and anti-viral properties. These properties might play protective roles in blocking SARS-CoV-2 replication and infection at least in part by enhancing endolysosome acidification, increasing autophagy, and inhibiting mTOR-signaling pathways. Several natural compounds have shown promise in suppressing SARS-CoV-2 infection in humans, but these compounds may be toxic at higher concentrations and doses [223-229]. Accordingly, a great deal more work is necessary to have confidence that phytochemicals can provide therapeutic benefit against SARS-CoV-2 infection and alter positively the clinical course of COVID-19.
Conflict of Interest
No conflict of interest.
All authors contributed equally to the writing of this manuscript.
This work was partly supported by NIH grant RO1 (MH119000).
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