key: cord-0748004-kkdqkqp4 authors: Khan, Nabab; Chen, Xuesong; Geiger, Jonathan D. title: Possible Therapeutic Use of Natural Compounds Against COVID-19 date: 2021 journal: J Cell Signal DOI: nan sha: 1c03de4f14539be92cc1e44b716626b34509e68f doc_id: 748004 cord_uid: kkdqkqp4 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. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-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] [4] [5] . SARS-CoV-2 infects cells by viral spike proteins interacting with host cells expressing angiotensin-converting enzyme 2 (ACE2) receptors; the virus enters host cells following transmembrane protease serine 2 (TMPRSS2)-mediated priming [6] [7] [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] [12] [13] [14] . Once released from endolysosomes into the cytosol, coronaviruses replicate in double membrane vesicles that resemble autophagosomes [15] [16] [17] [18] and when viral levels are sufficiently high pathological conditions develop including cytokine storms [19] [20] [21] [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 [25] , SLC38A9 [26] [27] [28] [29] , and mammalian target of rapamycin (mTOR) [30] [31] [32] [33] [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] [36] [37] [38] [39] 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] [46] [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] [59] [60] [61] [62] [63] [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 [63] . 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 [64] . 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. is catalyzed by ornithine decarboxylase [67] [68] [69] and from ornithine, the polyamines spermidine and spermine are generated [68] . Exogenously, ingestion of polyamines protected against age-related memory loss [70, 71] and rescued memory performance [71, 72] . The cardio-protective [73] , anti-inflammatory, and antioxidant [74] [75] [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] [79] [80] . Spermidine and spermine both inhibited SARS-CoV-2 infection and appeared to do so by inducing viral degradation in endolysosomes [15] . Resveratrol is a polyphenol with antioxidant and anti-inflammatory 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 [ [101, 102] properties as well as the ability to induce autophagy [103] . Phytoestrogens restrict PI3K/Akt/mTOR signaling pathways and this mechanism has been implicated in their ability to induce autophagy and kill cancer cells [104] [105] [106] . One estrogen, 17β-estradiol, is known already to suppress multiple viral infections including influenza [107] , rubella [108] , HIV-1 [109] , HSV-1 [110] , SARS-CoV [111] , and SARS-CoV-2 [112] [113] [114] . Trehalose, also known as tremalose and mycose, is a stable disaccharide assembled from two molecules of d-glucose [115] . 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] [117] [118] . Trehalose has antioxidant [119] and neuroprotective properties [119] [120] [121] [122] , and it has been shown to inhibit HIV-1 and mycobacterium tuberculosis (Mtb) co-infection by inducing the endolysosomal degradation pathway [123] . Further, trehalose induced mTOR-independent autophagy and suppressed cytomegalovirus infection in different cell types [124] . EGCG is a component of tea leaves [181] . EGCG has anti-oxidant properties and may prevent autoimmune diseases and cytokine storms [182] [183] [184] [185] [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-light-chain-enhancer of activated B cells) [187] [188] [189] [190] . EGCG upregulates AMPK activity in a dose-dependent manner and suppresses mTOR signaling in hepatoma cells [191] . A computer-based study has shown that EGCG is an ATP-competitive inhibitor of Akt/mTOR and enhances autophagy by AMPK activation [192] [193] [194] . Moreover, EGCG synergistically enhanced curcumin's effects on cancer cells by inducing autophagy through suppression of the Akt/ mTOR signaling pathway [195] . Naringenin is a flavorless flavanone; a predominant flavanone in various herbs and fruits including grapefruits, citrus, and tomatoes [196] [197] [198] . Naringenin has hepatoprotective, antiinflammatory, anti-mutagenic, anti-cancer, and anti-microbial [199] [200] [201] [202] [203] [204] effects and may control neurological, metabolic, rheumatological, and cardiovascular diseases [205] [206] [207] . Moreover, naringenin is an inhibitor of endolysosome two-pore channels (TPCs) [208] [209] [210] ; channels involved in SARS-CoV-2 and Ebola virus infections [211] [212] [213] as well as the ability of HIV-1 protein Tat to escape endolysosomes [214] . Naringenin can induce cancer cell death by promoting autophagy and downregulate the Akt/mTOR signaling pathway [215] [216] [217] [218] [219] . These finding suggest a possible use of naringenin against COVID-19 by targeting TPCs and the Akt/mTOR signaling pathway [220] [221] [222] . The COVID-19 pandemic is a global disaster with devasting social, behavioral, economic and health ramifications. Endolysosomes play important roles in regulating SARS-CoV-2 infection and thus might be targeted therapeutically against COVID-19. Relevant to COVID-19, endolysosomes are important regulators of innate immune responses and antigen presentation and phytochemicals have purported anti-inflammatory, antioxidant, 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] [224] [225] [226] [227] [228] [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. Restricts SARS-CoV in vivo [111] +++ Suggested as a suppressor of COVID-19 [112, 114, 224, [234] [235] [236] Estrogen therapy (NCT04539626) No effect on mTOR [124] Induces autophagy and lysosomal biogenesis by TFEB activation [120, 122] Potential anti-inflammatory [237] Potential target against COVID-19 [238] ++ Induces lysosomes acidification and autophagy by mucolipin-1 (TRPML1) activation to protect mycobacterium tuberculosis infection [123] Baicalin Negatively regulates mTOR signaling pathways [133] [134] [135] Autophagy inducer [133] Potential anti-inflammatory [239] [240] [241] Suppresses COVID-19 pathological condition in vivo, in vitro [137, [242] [243] [244] +++ Induces lysosomes acidification by promoting assembly of v-ATPase pump [132] Proposed for clinical trial (NCT03830684) Curcumin Negatively regulates mTOR signaling pathways [152] [153] [154] Autophagy inducer [59, 60] Potential anti-inflammatory [142, 143, 245] Proposed against COVID-19 [245] [246] [247] [248] +++ Proposed for clinical trial against COVID-19 (NCT04353310) Negatively regulates mTOR signaling pathways [161, 162] Autophagy inducer [160, 161] Potential anti-inflammatory [156, 249] Potential target against COVID-19 [168, [250] [251] [252] [253] +++ Proposed for clinical trial against COVID- 19 (NCT04377789) Negatively regulates mTOR signaling pathways [177] Autophagy inducer [176, 178] Potential anti-inflammatory [254] Potential target against COVID-19 (in silico) 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] [257] [258] +++ Identification of a novel coronavirus causing severe pneumonia in human: a descriptive study Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding The novel zoonotic COVID-19 pandemic: An expected global health concern 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