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LitCovid-PD-FMA-UBERON

{"project":"LitCovid-PD-FMA-UBERON","denotations":[{"id":"T6","span":{"begin":1933,"end":1939},"obj":"Body_part"},{"id":"T7","span":{"begin":6154,"end":6160},"obj":"Body_part"},{"id":"T8","span":{"begin":6168,"end":6173},"obj":"Body_part"},{"id":"T9","span":{"begin":7422,"end":7426},"obj":"Body_part"},{"id":"T10","span":{"begin":8985,"end":8990},"obj":"Body_part"},{"id":"T11","span":{"begin":9593,"end":9598},"obj":"Body_part"},{"id":"T12","span":{"begin":10386,"end":10393},"obj":"Body_part"}],"attributes":[{"id":"A6","pred":"fma_id","subj":"T6","obj":"http://purl.org/sig/ont/fma/fma9607"},{"id":"A7","pred":"fma_id","subj":"T7","obj":"http://purl.org/sig/ont/fma/fma7203"},{"id":"A8","pred":"fma_id","subj":"T8","obj":"http://purl.org/sig/ont/fma/fma68646"},{"id":"A9","pred":"fma_id","subj":"T9","obj":"http://purl.org/sig/ont/fma/fma68646"},{"id":"A10","pred":"fma_id","subj":"T10","obj":"http://purl.org/sig/ont/fma/fma68646"},{"id":"A11","pred":"fma_id","subj":"T11","obj":"http://purl.org/sig/ont/fma/fma68646"},{"id":"A12","pred":"fma_id","subj":"T12","obj":"http://purl.org/sig/ont/fma/fma67257"}],"text":"1. Introduction\nThe 2019 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a newly emerging respiratory illness. The epidemic started in December 2019 in Wuhan, China, and has rapidly spread throughout China and the world and is now a global pandemic. SARS-CoV-2 can be efficiently transmitted among humans and has shown a high degree of morbidity and mortality [1,2]. As of April 20, 2020, the worldwide number of infected individuals was 2,544,792, with as many as 175,694 deaths [3]. There are currently no approved vaccines available for the prevention of SARS-CoV-2 infection and only just recently, remdesivir has received “emergency use authorization” for treatment of COVID-19 in the United States; therefore, there is an urgent demand for potential chemotherapeutic agents to treat this disease.\nEssential oils have been screened against several pathogenic viruses (Table 1), including influenza and other respiratory viral infections. Influenza is an infectious respiratory disease caused by one of three types of influenza viruses, type A, type B, or type C [4]. The most significant in terms of human morbidity and mortality is influenza virus type A, which is found in several bird and mammal species [5]. Several different serotypes of influenza type A have caused global flu pandemics [6]: H1N1, which caused the Spanish flu in 1918 (40–50 million deaths worldwide) [7] and the swine flu in 2009 [8]; the Asian flu of 1957–1958 (ca. 1.5 million deaths worldwide) was caused by influenza A H2N2 [8]; serotype H3N2 caused the Hong Kong flu in 1968 [9]; and H5N1, which caused the bird flu in 2004 [10]. Influenza virus type B, however, is largely confined to human hosts [11].\nOne study evaluated the in vitro antiviral effect against influenza type A (H1N1) of commercial essential oils that included cinnamon (Cinnamomum zeylanicum), bergamot (Citrus bergamia), lemongrass (Cymbopogon flexuosus), thyme (Thymus vulgaris), and lavender (Lavandula angustifolia). The oils were tested in the liquid phase at a concentration of 0.3% and in the vapor phase. The oils of cinnamon, bergamot, thyme, and lemongrass displayed 100% inhibition of H1N1 in the liquid phase, while the inhibition for lavender essential oil was 85%. However, in the vapor phase, 100% inhibition was observed only for cinnamon leaf essential oil after 30 min of exposure. The bergamot, lemongrass, thyme, and lavender essential oils displayed inhibition rates of 95%, 90%, 70%, and 80%, respectively [12].\nCinnamomum zeylanicum leaf oil is characterized by eugenol (75–85%), followed by smaller amounts of linalool (1.6–8.5%), and benzyl benzoate (0.1–8.3%) [13,14,15]. Bergamot oil is rich in limonene (23–55%), linalool (2–37%), and linalyl acetate (12–41%), with lesser quantities of β-pinene (up to 10%) and γ-terpinene (up to 10%) [16,17,18,19,20]. Geranial (48–54%) and neral (29–33%) have been reported as the major components of C. flexuosus, but many chemotypes, cultivars, and variants have been reported for C. flexuosus [21,22].\nIn the literature, there have been at least 20 different chemotypes identified for thyme essential oil. The “typical” thyme essential oil presents a thymol content of 45% (range 31–50%), with significant concentrations of p-cymene (0.1–26.6%, average = 15.6%) and γ-terpinene (up to 22.8%, average = 9.3%). In addition, there are several other chemotypes of T. vulgaris rich in thymol and/or carvacrol [23]. Thymol has been identified as an anti-influenza agent against influenza type A and parainfluenza type 3 virus [24,25]. Lavandula angustifolia essential oil is rich in linalyl acetate (37.0–43.6%), linalool (19.7–39.1%), geraniol (up to 9.3%), β-caryophyllene (up to 5.1%), terpinen-4-ol (up to 14.9%), lavandulyl acetate (up to 5.5%), and borneol (up to 6.4%) [26,27,28,29].\nAnother essential oil with notable anti-influenza effects is tea tree, which is extracted from the leaves of Melaleuca alternifolia (Myrtaceae). Commercial tea tree oil is composed of terpinen-4-ol (30–48%), γ-terpinene (10–28%), α-terpinene (5–13%), 1,8-cineole (up to 15%), terpinolene (1.5–5%), p-cymene (0.5–12%), α-pinene (1–6%), and α-terpineol (1.5–8%) [30]. Tea tree oil showed 100% inhibition of influenza type A (H1N1) virus at 0.01% concentration and a median inhibitory concentration (IC50) of 6 μg/mL [31,32]. In addition, 30 min exposure of type A (H11N9) virus to tea tree oil vapor caused 100% inhibition [33]. The tea tree oil components, terpinen-4-ol, terpinolene, and α-terpineol, have shown anti-influenza virus activity against type A (H1N1), with IC50 values of 25, 12, and 250 μg/mL, respectively. α-Terpinene, γ-terpinene, and p-cymene were inactive, however [31].\nAvian influenza viruses (H5N1) exhibit both high and low virulence in numerous mammalian species, highlighting the connection between the route of inoculation and virus pathogenicity [34]. Since 2003, there have been over 600 documented cases of human infection with H5N1 viruses, with most cases among young, previously healthy individuals [35]. The essential oils extracted from Citrus reshni leaves and peel (unripe and ripe fruits) were tested against H5N1 virus by plaque reduction assay. The oils showed moderate inhibition of the H5N1 virus at a concentration of 2.5 μL/mL. Sabinene (40.5%), linalool (23.3%), and terpinen-4-ol (8.3%) were the main constituents in the leaf oil while limonene (82.4%, 91.6%) was the main compound in the fruit peel essential oils (unripe and ripe, respectively) [36].\nThe essential oil of leaves of Fortunella margarita is rich in the sesquiterpenoids β-eudesmol (28.3%), α-muurolene (10.3%), β-gurjunene (10.0%), γ-eudesmol (8.4%), and γ-muurolene (6.6%) while the essential oil extracted from the fruits showed monterpenoids as the main components, α-terpineol (55.5%), carvone (5.7%), and carveol (5.5%). Both samples were tested for antiviral activity against avian influenza (H5N1) virus, and the obtained results revealed that the fruit essential oil was more effective (80% virus inhibition by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay using Madin−Darby canine kidney (MDCK) cells for virus propagation). The IC50 values obtained for the leaf and fruit essential oils were 38.89 and 6.77 μg/mL, respectively [53].\nDengue fever, a mosquito−borne disease, is caused by dengue virus (DENV) which includes four major serotypes (DENV-1, -2, -3, and -4). Some serotypes cause more severe diseases than others; severe dengue is associated with secondary infections by a different serotype. Dengue disease is a major public health problem in developing tropical countries and has being continuously spreading to new geographical areas [92]. The essential oils of two species of Lippia were assayed against four dengue serotypes (DENV-1, DENV-2, DENV-3, DENV-4) [61]. The IC50 values for Lippia alba oil, rich in carvone (39.7%), limonene (30.6%), and bicyclosesquiphellandrene (8.9%), were between 0.4 and 32.6 μg/mL. However, the Lippia citrodora essential oil, composed of geranial (18.9%), neral (15.6%), limonene (10.7%), and 1,8-cineole (5.0%), showed the best activity, with IC50 values varying from 1.9 to 33.7 μg/mL. No viral inhibitory effect was observed by addition of the essential oil after virus adsorption; the inhibitory effect of the essential oil seemed to cause direct virus inactivation before adsorption on the host cell.\nThe essential oils of seven aromatic plants from Córdoba, San Luis, and San Juan provinces (Argentina) were screened for cytotoxicity and in vitro inhibitory activity against dengue virus type 2 (DENV−2) [38]. The oils of Jungia polita and Buddleja cordobensis were composed of caryophyllene oxide (9.18%, 32.1%) and β-caryophyllene (8.13%, 16.5%) as the major compounds. However, these oils displayed different IC50 values (86.4 and 39.8 μg/mL, respectively). The other samples were composed mostly of monoterpenes and displayed lower activity, except Pectis odorata oil, which presented limonene (50.2%), neral (27.2%), and geranial (23.6%) as the major compounds and an IC50 value of 39.6 μg/mL. In addition, the essential oils of Artemisia mendozana, rich in camphor (22.4%), artemisole (11.7%), and artemisia alcohol (10.8%); Gailardia megapotamica composed of β-pinene (35.5%), spathulenol (10.7%), and germacrene D (6.8%); and Heterothalamus alienus characterized by β-pinene (35.5%), spathulenol (10.7%), and germacrene D (6.8%), showed an average IC50 value of 130.63 μg/mL.\nYellow fever (YF), caused by yellow fever virus (YFV), has historically been considered one of the most dangerous infectious diseases. YFV is transmitted to humans via mosquitoes of the Haemogogus, Sabethes, and Aedes genera. Annually, there are approximately 80,000–200,000 YFV cases worldwide, with a case fatality rate (CFR) ranging from 20–60% [93,94]. Essential oils of Lippia species and their main compounds have been tested against yellow fever virus (YFV) in Vero cells. The oil of Lippia origanoides showed carvacrol (44.0%), thymol (15.0%), and γ-terpinene (10.0%) as the main compounds and displayed 100% inhibition at a concentration of 11.1 μg/mL [43]. However, in the same study, the oil of L. alba displayed 100% inhibition at a concentration of 100.0 μg/mL. The major compounds were carvone (51.0%), limonene (33.0%), and bicyclosesquiphellandrene (7.0%). The essential oil of L. alba with a similar chemical composition, carvone (39.7%), limonene (30.6%), and bicyclosesquiphellandrene (8.9%), displayed an IC50 value of 4.3 μg/mL against YFV when tested in Vero cells using the MTT assay [62]. The essential oil of L. citriodora, dominated by geranial (18.9%), neral (15.6%), and limonene (10.7%), did not display a statistical difference in comparison to citral, with IC50 values of 19.4 and 17.6 μg/mL, respectively [62].\nIn addition to essential oils, several individual essential oil components have been screened for antiviral activity (Table 2).\nBecause of the activities of several essential oils and essential oil components against human pathogenic viruses, we hypothesized that essential oil components may be potentially useful as antiviral agents against SARS-CoV-2. In this work, we carried out a molecular docking analysis of the major components of essential oils that exhibit antiviral activity (Table 1 and Table 2) with known SARS-CoV-2 protein targets."}

LitCovid-PD-UBERON

{"project":"LitCovid-PD-UBERON","denotations":[{"id":"T1","span":{"begin":1933,"end":1939},"obj":"Body_part"},{"id":"T2","span":{"begin":6154,"end":6160},"obj":"Body_part"}],"attributes":[{"id":"A1","pred":"uberon_id","subj":"T1","obj":"http://purl.obolibrary.org/obo/UBERON_0002370"},{"id":"A2","pred":"uberon_id","subj":"T2","obj":"http://purl.obolibrary.org/obo/UBERON_0002113"}],"text":"1. Introduction\nThe 2019 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a newly emerging respiratory illness. The epidemic started in December 2019 in Wuhan, China, and has rapidly spread throughout China and the world and is now a global pandemic. SARS-CoV-2 can be efficiently transmitted among humans and has shown a high degree of morbidity and mortality [1,2]. As of April 20, 2020, the worldwide number of infected individuals was 2,544,792, with as many as 175,694 deaths [3]. There are currently no approved vaccines available for the prevention of SARS-CoV-2 infection and only just recently, remdesivir has received “emergency use authorization” for treatment of COVID-19 in the United States; therefore, there is an urgent demand for potential chemotherapeutic agents to treat this disease.\nEssential oils have been screened against several pathogenic viruses (Table 1), including influenza and other respiratory viral infections. Influenza is an infectious respiratory disease caused by one of three types of influenza viruses, type A, type B, or type C [4]. The most significant in terms of human morbidity and mortality is influenza virus type A, which is found in several bird and mammal species [5]. Several different serotypes of influenza type A have caused global flu pandemics [6]: H1N1, which caused the Spanish flu in 1918 (40–50 million deaths worldwide) [7] and the swine flu in 2009 [8]; the Asian flu of 1957–1958 (ca. 1.5 million deaths worldwide) was caused by influenza A H2N2 [8]; serotype H3N2 caused the Hong Kong flu in 1968 [9]; and H5N1, which caused the bird flu in 2004 [10]. Influenza virus type B, however, is largely confined to human hosts [11].\nOne study evaluated the in vitro antiviral effect against influenza type A (H1N1) of commercial essential oils that included cinnamon (Cinnamomum zeylanicum), bergamot (Citrus bergamia), lemongrass (Cymbopogon flexuosus), thyme (Thymus vulgaris), and lavender (Lavandula angustifolia). The oils were tested in the liquid phase at a concentration of 0.3% and in the vapor phase. The oils of cinnamon, bergamot, thyme, and lemongrass displayed 100% inhibition of H1N1 in the liquid phase, while the inhibition for lavender essential oil was 85%. However, in the vapor phase, 100% inhibition was observed only for cinnamon leaf essential oil after 30 min of exposure. The bergamot, lemongrass, thyme, and lavender essential oils displayed inhibition rates of 95%, 90%, 70%, and 80%, respectively [12].\nCinnamomum zeylanicum leaf oil is characterized by eugenol (75–85%), followed by smaller amounts of linalool (1.6–8.5%), and benzyl benzoate (0.1–8.3%) [13,14,15]. Bergamot oil is rich in limonene (23–55%), linalool (2–37%), and linalyl acetate (12–41%), with lesser quantities of β-pinene (up to 10%) and γ-terpinene (up to 10%) [16,17,18,19,20]. Geranial (48–54%) and neral (29–33%) have been reported as the major components of C. flexuosus, but many chemotypes, cultivars, and variants have been reported for C. flexuosus [21,22].\nIn the literature, there have been at least 20 different chemotypes identified for thyme essential oil. The “typical” thyme essential oil presents a thymol content of 45% (range 31–50%), with significant concentrations of p-cymene (0.1–26.6%, average = 15.6%) and γ-terpinene (up to 22.8%, average = 9.3%). In addition, there are several other chemotypes of T. vulgaris rich in thymol and/or carvacrol [23]. Thymol has been identified as an anti-influenza agent against influenza type A and parainfluenza type 3 virus [24,25]. Lavandula angustifolia essential oil is rich in linalyl acetate (37.0–43.6%), linalool (19.7–39.1%), geraniol (up to 9.3%), β-caryophyllene (up to 5.1%), terpinen-4-ol (up to 14.9%), lavandulyl acetate (up to 5.5%), and borneol (up to 6.4%) [26,27,28,29].\nAnother essential oil with notable anti-influenza effects is tea tree, which is extracted from the leaves of Melaleuca alternifolia (Myrtaceae). Commercial tea tree oil is composed of terpinen-4-ol (30–48%), γ-terpinene (10–28%), α-terpinene (5–13%), 1,8-cineole (up to 15%), terpinolene (1.5–5%), p-cymene (0.5–12%), α-pinene (1–6%), and α-terpineol (1.5–8%) [30]. Tea tree oil showed 100% inhibition of influenza type A (H1N1) virus at 0.01% concentration and a median inhibitory concentration (IC50) of 6 μg/mL [31,32]. In addition, 30 min exposure of type A (H11N9) virus to tea tree oil vapor caused 100% inhibition [33]. The tea tree oil components, terpinen-4-ol, terpinolene, and α-terpineol, have shown anti-influenza virus activity against type A (H1N1), with IC50 values of 25, 12, and 250 μg/mL, respectively. α-Terpinene, γ-terpinene, and p-cymene were inactive, however [31].\nAvian influenza viruses (H5N1) exhibit both high and low virulence in numerous mammalian species, highlighting the connection between the route of inoculation and virus pathogenicity [34]. Since 2003, there have been over 600 documented cases of human infection with H5N1 viruses, with most cases among young, previously healthy individuals [35]. The essential oils extracted from Citrus reshni leaves and peel (unripe and ripe fruits) were tested against H5N1 virus by plaque reduction assay. The oils showed moderate inhibition of the H5N1 virus at a concentration of 2.5 μL/mL. Sabinene (40.5%), linalool (23.3%), and terpinen-4-ol (8.3%) were the main constituents in the leaf oil while limonene (82.4%, 91.6%) was the main compound in the fruit peel essential oils (unripe and ripe, respectively) [36].\nThe essential oil of leaves of Fortunella margarita is rich in the sesquiterpenoids β-eudesmol (28.3%), α-muurolene (10.3%), β-gurjunene (10.0%), γ-eudesmol (8.4%), and γ-muurolene (6.6%) while the essential oil extracted from the fruits showed monterpenoids as the main components, α-terpineol (55.5%), carvone (5.7%), and carveol (5.5%). Both samples were tested for antiviral activity against avian influenza (H5N1) virus, and the obtained results revealed that the fruit essential oil was more effective (80% virus inhibition by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay using Madin−Darby canine kidney (MDCK) cells for virus propagation). The IC50 values obtained for the leaf and fruit essential oils were 38.89 and 6.77 μg/mL, respectively [53].\nDengue fever, a mosquito−borne disease, is caused by dengue virus (DENV) which includes four major serotypes (DENV-1, -2, -3, and -4). Some serotypes cause more severe diseases than others; severe dengue is associated with secondary infections by a different serotype. Dengue disease is a major public health problem in developing tropical countries and has being continuously spreading to new geographical areas [92]. The essential oils of two species of Lippia were assayed against four dengue serotypes (DENV-1, DENV-2, DENV-3, DENV-4) [61]. The IC50 values for Lippia alba oil, rich in carvone (39.7%), limonene (30.6%), and bicyclosesquiphellandrene (8.9%), were between 0.4 and 32.6 μg/mL. However, the Lippia citrodora essential oil, composed of geranial (18.9%), neral (15.6%), limonene (10.7%), and 1,8-cineole (5.0%), showed the best activity, with IC50 values varying from 1.9 to 33.7 μg/mL. No viral inhibitory effect was observed by addition of the essential oil after virus adsorption; the inhibitory effect of the essential oil seemed to cause direct virus inactivation before adsorption on the host cell.\nThe essential oils of seven aromatic plants from Córdoba, San Luis, and San Juan provinces (Argentina) were screened for cytotoxicity and in vitro inhibitory activity against dengue virus type 2 (DENV−2) [38]. The oils of Jungia polita and Buddleja cordobensis were composed of caryophyllene oxide (9.18%, 32.1%) and β-caryophyllene (8.13%, 16.5%) as the major compounds. However, these oils displayed different IC50 values (86.4 and 39.8 μg/mL, respectively). The other samples were composed mostly of monoterpenes and displayed lower activity, except Pectis odorata oil, which presented limonene (50.2%), neral (27.2%), and geranial (23.6%) as the major compounds and an IC50 value of 39.6 μg/mL. In addition, the essential oils of Artemisia mendozana, rich in camphor (22.4%), artemisole (11.7%), and artemisia alcohol (10.8%); Gailardia megapotamica composed of β-pinene (35.5%), spathulenol (10.7%), and germacrene D (6.8%); and Heterothalamus alienus characterized by β-pinene (35.5%), spathulenol (10.7%), and germacrene D (6.8%), showed an average IC50 value of 130.63 μg/mL.\nYellow fever (YF), caused by yellow fever virus (YFV), has historically been considered one of the most dangerous infectious diseases. YFV is transmitted to humans via mosquitoes of the Haemogogus, Sabethes, and Aedes genera. Annually, there are approximately 80,000–200,000 YFV cases worldwide, with a case fatality rate (CFR) ranging from 20–60% [93,94]. Essential oils of Lippia species and their main compounds have been tested against yellow fever virus (YFV) in Vero cells. The oil of Lippia origanoides showed carvacrol (44.0%), thymol (15.0%), and γ-terpinene (10.0%) as the main compounds and displayed 100% inhibition at a concentration of 11.1 μg/mL [43]. However, in the same study, the oil of L. alba displayed 100% inhibition at a concentration of 100.0 μg/mL. The major compounds were carvone (51.0%), limonene (33.0%), and bicyclosesquiphellandrene (7.0%). The essential oil of L. alba with a similar chemical composition, carvone (39.7%), limonene (30.6%), and bicyclosesquiphellandrene (8.9%), displayed an IC50 value of 4.3 μg/mL against YFV when tested in Vero cells using the MTT assay [62]. The essential oil of L. citriodora, dominated by geranial (18.9%), neral (15.6%), and limonene (10.7%), did not display a statistical difference in comparison to citral, with IC50 values of 19.4 and 17.6 μg/mL, respectively [62].\nIn addition to essential oils, several individual essential oil components have been screened for antiviral activity (Table 2).\nBecause of the activities of several essential oils and essential oil components against human pathogenic viruses, we hypothesized that essential oil components may be potentially useful as antiviral agents against SARS-CoV-2. In this work, we carried out a molecular docking analysis of the major components of essential oils that exhibit antiviral activity (Table 1 and Table 2) with known SARS-CoV-2 protein targets."}

LitCovid-PubTator

LitCovid-PD-MONDO

LitCovid-PD-CLO

LitCovid-PD-CHEBI

LitCovid-PD-HP

{"project":"LitCovid-PD-HP","denotations":[{"id":"T1","span":{"begin":106,"end":125},"obj":"Phenotype"},{"id":"T2","span":{"begin":6314,"end":6319},"obj":"Phenotype"},{"id":"T3","span":{"begin":8519,"end":8524},"obj":"Phenotype"},{"id":"T4","span":{"begin":8548,"end":8553},"obj":"Phenotype"},{"id":"T5","span":{"begin":8959,"end":8964},"obj":"Phenotype"}],"attributes":[{"id":"A1","pred":"hp_id","subj":"T1","obj":"http://purl.obolibrary.org/obo/HP_0002086"},{"id":"A2","pred":"hp_id","subj":"T2","obj":"http://purl.obolibrary.org/obo/HP_0001945"},{"id":"A3","pred":"hp_id","subj":"T3","obj":"http://purl.obolibrary.org/obo/HP_0001945"},{"id":"A4","pred":"hp_id","subj":"T4","obj":"http://purl.obolibrary.org/obo/HP_0001945"},{"id":"A5","pred":"hp_id","subj":"T5","obj":"http://purl.obolibrary.org/obo/HP_0001945"}],"text":"1. Introduction\nThe 2019 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a newly emerging respiratory illness. The epidemic started in December 2019 in Wuhan, China, and has rapidly spread throughout China and the world and is now a global pandemic. SARS-CoV-2 can be efficiently transmitted among humans and has shown a high degree of morbidity and mortality [1,2]. As of April 20, 2020, the worldwide number of infected individuals was 2,544,792, with as many as 175,694 deaths [3]. There are currently no approved vaccines available for the prevention of SARS-CoV-2 infection and only just recently, remdesivir has received “emergency use authorization” for treatment of COVID-19 in the United States; therefore, there is an urgent demand for potential chemotherapeutic agents to treat this disease.\nEssential oils have been screened against several pathogenic viruses (Table 1), including influenza and other respiratory viral infections. Influenza is an infectious respiratory disease caused by one of three types of influenza viruses, type A, type B, or type C [4]. The most significant in terms of human morbidity and mortality is influenza virus type A, which is found in several bird and mammal species [5]. Several different serotypes of influenza type A have caused global flu pandemics [6]: H1N1, which caused the Spanish flu in 1918 (40–50 million deaths worldwide) [7] and the swine flu in 2009 [8]; the Asian flu of 1957–1958 (ca. 1.5 million deaths worldwide) was caused by influenza A H2N2 [8]; serotype H3N2 caused the Hong Kong flu in 1968 [9]; and H5N1, which caused the bird flu in 2004 [10]. Influenza virus type B, however, is largely confined to human hosts [11].\nOne study evaluated the in vitro antiviral effect against influenza type A (H1N1) of commercial essential oils that included cinnamon (Cinnamomum zeylanicum), bergamot (Citrus bergamia), lemongrass (Cymbopogon flexuosus), thyme (Thymus vulgaris), and lavender (Lavandula angustifolia). The oils were tested in the liquid phase at a concentration of 0.3% and in the vapor phase. The oils of cinnamon, bergamot, thyme, and lemongrass displayed 100% inhibition of H1N1 in the liquid phase, while the inhibition for lavender essential oil was 85%. However, in the vapor phase, 100% inhibition was observed only for cinnamon leaf essential oil after 30 min of exposure. The bergamot, lemongrass, thyme, and lavender essential oils displayed inhibition rates of 95%, 90%, 70%, and 80%, respectively [12].\nCinnamomum zeylanicum leaf oil is characterized by eugenol (75–85%), followed by smaller amounts of linalool (1.6–8.5%), and benzyl benzoate (0.1–8.3%) [13,14,15]. Bergamot oil is rich in limonene (23–55%), linalool (2–37%), and linalyl acetate (12–41%), with lesser quantities of β-pinene (up to 10%) and γ-terpinene (up to 10%) [16,17,18,19,20]. Geranial (48–54%) and neral (29–33%) have been reported as the major components of C. flexuosus, but many chemotypes, cultivars, and variants have been reported for C. flexuosus [21,22].\nIn the literature, there have been at least 20 different chemotypes identified for thyme essential oil. The “typical” thyme essential oil presents a thymol content of 45% (range 31–50%), with significant concentrations of p-cymene (0.1–26.6%, average = 15.6%) and γ-terpinene (up to 22.8%, average = 9.3%). In addition, there are several other chemotypes of T. vulgaris rich in thymol and/or carvacrol [23]. Thymol has been identified as an anti-influenza agent against influenza type A and parainfluenza type 3 virus [24,25]. Lavandula angustifolia essential oil is rich in linalyl acetate (37.0–43.6%), linalool (19.7–39.1%), geraniol (up to 9.3%), β-caryophyllene (up to 5.1%), terpinen-4-ol (up to 14.9%), lavandulyl acetate (up to 5.5%), and borneol (up to 6.4%) [26,27,28,29].\nAnother essential oil with notable anti-influenza effects is tea tree, which is extracted from the leaves of Melaleuca alternifolia (Myrtaceae). Commercial tea tree oil is composed of terpinen-4-ol (30–48%), γ-terpinene (10–28%), α-terpinene (5–13%), 1,8-cineole (up to 15%), terpinolene (1.5–5%), p-cymene (0.5–12%), α-pinene (1–6%), and α-terpineol (1.5–8%) [30]. Tea tree oil showed 100% inhibition of influenza type A (H1N1) virus at 0.01% concentration and a median inhibitory concentration (IC50) of 6 μg/mL [31,32]. In addition, 30 min exposure of type A (H11N9) virus to tea tree oil vapor caused 100% inhibition [33]. The tea tree oil components, terpinen-4-ol, terpinolene, and α-terpineol, have shown anti-influenza virus activity against type A (H1N1), with IC50 values of 25, 12, and 250 μg/mL, respectively. α-Terpinene, γ-terpinene, and p-cymene were inactive, however [31].\nAvian influenza viruses (H5N1) exhibit both high and low virulence in numerous mammalian species, highlighting the connection between the route of inoculation and virus pathogenicity [34]. Since 2003, there have been over 600 documented cases of human infection with H5N1 viruses, with most cases among young, previously healthy individuals [35]. The essential oils extracted from Citrus reshni leaves and peel (unripe and ripe fruits) were tested against H5N1 virus by plaque reduction assay. The oils showed moderate inhibition of the H5N1 virus at a concentration of 2.5 μL/mL. Sabinene (40.5%), linalool (23.3%), and terpinen-4-ol (8.3%) were the main constituents in the leaf oil while limonene (82.4%, 91.6%) was the main compound in the fruit peel essential oils (unripe and ripe, respectively) [36].\nThe essential oil of leaves of Fortunella margarita is rich in the sesquiterpenoids β-eudesmol (28.3%), α-muurolene (10.3%), β-gurjunene (10.0%), γ-eudesmol (8.4%), and γ-muurolene (6.6%) while the essential oil extracted from the fruits showed monterpenoids as the main components, α-terpineol (55.5%), carvone (5.7%), and carveol (5.5%). Both samples were tested for antiviral activity against avian influenza (H5N1) virus, and the obtained results revealed that the fruit essential oil was more effective (80% virus inhibition by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay using Madin−Darby canine kidney (MDCK) cells for virus propagation). The IC50 values obtained for the leaf and fruit essential oils were 38.89 and 6.77 μg/mL, respectively [53].\nDengue fever, a mosquito−borne disease, is caused by dengue virus (DENV) which includes four major serotypes (DENV-1, -2, -3, and -4). Some serotypes cause more severe diseases than others; severe dengue is associated with secondary infections by a different serotype. Dengue disease is a major public health problem in developing tropical countries and has being continuously spreading to new geographical areas [92]. The essential oils of two species of Lippia were assayed against four dengue serotypes (DENV-1, DENV-2, DENV-3, DENV-4) [61]. The IC50 values for Lippia alba oil, rich in carvone (39.7%), limonene (30.6%), and bicyclosesquiphellandrene (8.9%), were between 0.4 and 32.6 μg/mL. However, the Lippia citrodora essential oil, composed of geranial (18.9%), neral (15.6%), limonene (10.7%), and 1,8-cineole (5.0%), showed the best activity, with IC50 values varying from 1.9 to 33.7 μg/mL. No viral inhibitory effect was observed by addition of the essential oil after virus adsorption; the inhibitory effect of the essential oil seemed to cause direct virus inactivation before adsorption on the host cell.\nThe essential oils of seven aromatic plants from Córdoba, San Luis, and San Juan provinces (Argentina) were screened for cytotoxicity and in vitro inhibitory activity against dengue virus type 2 (DENV−2) [38]. The oils of Jungia polita and Buddleja cordobensis were composed of caryophyllene oxide (9.18%, 32.1%) and β-caryophyllene (8.13%, 16.5%) as the major compounds. However, these oils displayed different IC50 values (86.4 and 39.8 μg/mL, respectively). The other samples were composed mostly of monoterpenes and displayed lower activity, except Pectis odorata oil, which presented limonene (50.2%), neral (27.2%), and geranial (23.6%) as the major compounds and an IC50 value of 39.6 μg/mL. In addition, the essential oils of Artemisia mendozana, rich in camphor (22.4%), artemisole (11.7%), and artemisia alcohol (10.8%); Gailardia megapotamica composed of β-pinene (35.5%), spathulenol (10.7%), and germacrene D (6.8%); and Heterothalamus alienus characterized by β-pinene (35.5%), spathulenol (10.7%), and germacrene D (6.8%), showed an average IC50 value of 130.63 μg/mL.\nYellow fever (YF), caused by yellow fever virus (YFV), has historically been considered one of the most dangerous infectious diseases. YFV is transmitted to humans via mosquitoes of the Haemogogus, Sabethes, and Aedes genera. Annually, there are approximately 80,000–200,000 YFV cases worldwide, with a case fatality rate (CFR) ranging from 20–60% [93,94]. Essential oils of Lippia species and their main compounds have been tested against yellow fever virus (YFV) in Vero cells. The oil of Lippia origanoides showed carvacrol (44.0%), thymol (15.0%), and γ-terpinene (10.0%) as the main compounds and displayed 100% inhibition at a concentration of 11.1 μg/mL [43]. However, in the same study, the oil of L. alba displayed 100% inhibition at a concentration of 100.0 μg/mL. The major compounds were carvone (51.0%), limonene (33.0%), and bicyclosesquiphellandrene (7.0%). The essential oil of L. alba with a similar chemical composition, carvone (39.7%), limonene (30.6%), and bicyclosesquiphellandrene (8.9%), displayed an IC50 value of 4.3 μg/mL against YFV when tested in Vero cells using the MTT assay [62]. The essential oil of L. citriodora, dominated by geranial (18.9%), neral (15.6%), and limonene (10.7%), did not display a statistical difference in comparison to citral, with IC50 values of 19.4 and 17.6 μg/mL, respectively [62].\nIn addition to essential oils, several individual essential oil components have been screened for antiviral activity (Table 2).\nBecause of the activities of several essential oils and essential oil components against human pathogenic viruses, we hypothesized that essential oil components may be potentially useful as antiviral agents against SARS-CoV-2. In this work, we carried out a molecular docking analysis of the major components of essential oils that exhibit antiviral activity (Table 1 and Table 2) with known SARS-CoV-2 protein targets."}

LitCovid-PD-GO-BP

{"project":"LitCovid-PD-GO-BP","denotations":[{"id":"T3","span":{"begin":941,"end":957},"obj":"http://purl.obolibrary.org/obo/GO_0016032"},{"id":"T4","span":{"begin":4768,"end":4777},"obj":"http://purl.obolibrary.org/obo/GO_0016032"},{"id":"T5","span":{"begin":4768,"end":4777},"obj":"http://purl.obolibrary.org/obo/GO_0009405"},{"id":"T6","span":{"begin":10386,"end":10401},"obj":"http://purl.obolibrary.org/obo/GO_0006605"}],"text":"1. Introduction\nThe 2019 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a newly emerging respiratory illness. The epidemic started in December 2019 in Wuhan, China, and has rapidly spread throughout China and the world and is now a global pandemic. SARS-CoV-2 can be efficiently transmitted among humans and has shown a high degree of morbidity and mortality [1,2]. As of April 20, 2020, the worldwide number of infected individuals was 2,544,792, with as many as 175,694 deaths [3]. There are currently no approved vaccines available for the prevention of SARS-CoV-2 infection and only just recently, remdesivir has received “emergency use authorization” for treatment of COVID-19 in the United States; therefore, there is an urgent demand for potential chemotherapeutic agents to treat this disease.\nEssential oils have been screened against several pathogenic viruses (Table 1), including influenza and other respiratory viral infections. Influenza is an infectious respiratory disease caused by one of three types of influenza viruses, type A, type B, or type C [4]. The most significant in terms of human morbidity and mortality is influenza virus type A, which is found in several bird and mammal species [5]. Several different serotypes of influenza type A have caused global flu pandemics [6]: H1N1, which caused the Spanish flu in 1918 (40–50 million deaths worldwide) [7] and the swine flu in 2009 [8]; the Asian flu of 1957–1958 (ca. 1.5 million deaths worldwide) was caused by influenza A H2N2 [8]; serotype H3N2 caused the Hong Kong flu in 1968 [9]; and H5N1, which caused the bird flu in 2004 [10]. Influenza virus type B, however, is largely confined to human hosts [11].\nOne study evaluated the in vitro antiviral effect against influenza type A (H1N1) of commercial essential oils that included cinnamon (Cinnamomum zeylanicum), bergamot (Citrus bergamia), lemongrass (Cymbopogon flexuosus), thyme (Thymus vulgaris), and lavender (Lavandula angustifolia). The oils were tested in the liquid phase at a concentration of 0.3% and in the vapor phase. The oils of cinnamon, bergamot, thyme, and lemongrass displayed 100% inhibition of H1N1 in the liquid phase, while the inhibition for lavender essential oil was 85%. However, in the vapor phase, 100% inhibition was observed only for cinnamon leaf essential oil after 30 min of exposure. The bergamot, lemongrass, thyme, and lavender essential oils displayed inhibition rates of 95%, 90%, 70%, and 80%, respectively [12].\nCinnamomum zeylanicum leaf oil is characterized by eugenol (75–85%), followed by smaller amounts of linalool (1.6–8.5%), and benzyl benzoate (0.1–8.3%) [13,14,15]. Bergamot oil is rich in limonene (23–55%), linalool (2–37%), and linalyl acetate (12–41%), with lesser quantities of β-pinene (up to 10%) and γ-terpinene (up to 10%) [16,17,18,19,20]. Geranial (48–54%) and neral (29–33%) have been reported as the major components of C. flexuosus, but many chemotypes, cultivars, and variants have been reported for C. flexuosus [21,22].\nIn the literature, there have been at least 20 different chemotypes identified for thyme essential oil. The “typical” thyme essential oil presents a thymol content of 45% (range 31–50%), with significant concentrations of p-cymene (0.1–26.6%, average = 15.6%) and γ-terpinene (up to 22.8%, average = 9.3%). In addition, there are several other chemotypes of T. vulgaris rich in thymol and/or carvacrol [23]. Thymol has been identified as an anti-influenza agent against influenza type A and parainfluenza type 3 virus [24,25]. Lavandula angustifolia essential oil is rich in linalyl acetate (37.0–43.6%), linalool (19.7–39.1%), geraniol (up to 9.3%), β-caryophyllene (up to 5.1%), terpinen-4-ol (up to 14.9%), lavandulyl acetate (up to 5.5%), and borneol (up to 6.4%) [26,27,28,29].\nAnother essential oil with notable anti-influenza effects is tea tree, which is extracted from the leaves of Melaleuca alternifolia (Myrtaceae). Commercial tea tree oil is composed of terpinen-4-ol (30–48%), γ-terpinene (10–28%), α-terpinene (5–13%), 1,8-cineole (up to 15%), terpinolene (1.5–5%), p-cymene (0.5–12%), α-pinene (1–6%), and α-terpineol (1.5–8%) [30]. Tea tree oil showed 100% inhibition of influenza type A (H1N1) virus at 0.01% concentration and a median inhibitory concentration (IC50) of 6 μg/mL [31,32]. In addition, 30 min exposure of type A (H11N9) virus to tea tree oil vapor caused 100% inhibition [33]. The tea tree oil components, terpinen-4-ol, terpinolene, and α-terpineol, have shown anti-influenza virus activity against type A (H1N1), with IC50 values of 25, 12, and 250 μg/mL, respectively. α-Terpinene, γ-terpinene, and p-cymene were inactive, however [31].\nAvian influenza viruses (H5N1) exhibit both high and low virulence in numerous mammalian species, highlighting the connection between the route of inoculation and virus pathogenicity [34]. Since 2003, there have been over 600 documented cases of human infection with H5N1 viruses, with most cases among young, previously healthy individuals [35]. The essential oils extracted from Citrus reshni leaves and peel (unripe and ripe fruits) were tested against H5N1 virus by plaque reduction assay. The oils showed moderate inhibition of the H5N1 virus at a concentration of 2.5 μL/mL. Sabinene (40.5%), linalool (23.3%), and terpinen-4-ol (8.3%) were the main constituents in the leaf oil while limonene (82.4%, 91.6%) was the main compound in the fruit peel essential oils (unripe and ripe, respectively) [36].\nThe essential oil of leaves of Fortunella margarita is rich in the sesquiterpenoids β-eudesmol (28.3%), α-muurolene (10.3%), β-gurjunene (10.0%), γ-eudesmol (8.4%), and γ-muurolene (6.6%) while the essential oil extracted from the fruits showed monterpenoids as the main components, α-terpineol (55.5%), carvone (5.7%), and carveol (5.5%). Both samples were tested for antiviral activity against avian influenza (H5N1) virus, and the obtained results revealed that the fruit essential oil was more effective (80% virus inhibition by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay using Madin−Darby canine kidney (MDCK) cells for virus propagation). The IC50 values obtained for the leaf and fruit essential oils were 38.89 and 6.77 μg/mL, respectively [53].\nDengue fever, a mosquito−borne disease, is caused by dengue virus (DENV) which includes four major serotypes (DENV-1, -2, -3, and -4). Some serotypes cause more severe diseases than others; severe dengue is associated with secondary infections by a different serotype. Dengue disease is a major public health problem in developing tropical countries and has being continuously spreading to new geographical areas [92]. The essential oils of two species of Lippia were assayed against four dengue serotypes (DENV-1, DENV-2, DENV-3, DENV-4) [61]. The IC50 values for Lippia alba oil, rich in carvone (39.7%), limonene (30.6%), and bicyclosesquiphellandrene (8.9%), were between 0.4 and 32.6 μg/mL. However, the Lippia citrodora essential oil, composed of geranial (18.9%), neral (15.6%), limonene (10.7%), and 1,8-cineole (5.0%), showed the best activity, with IC50 values varying from 1.9 to 33.7 μg/mL. No viral inhibitory effect was observed by addition of the essential oil after virus adsorption; the inhibitory effect of the essential oil seemed to cause direct virus inactivation before adsorption on the host cell.\nThe essential oils of seven aromatic plants from Córdoba, San Luis, and San Juan provinces (Argentina) were screened for cytotoxicity and in vitro inhibitory activity against dengue virus type 2 (DENV−2) [38]. The oils of Jungia polita and Buddleja cordobensis were composed of caryophyllene oxide (9.18%, 32.1%) and β-caryophyllene (8.13%, 16.5%) as the major compounds. However, these oils displayed different IC50 values (86.4 and 39.8 μg/mL, respectively). The other samples were composed mostly of monoterpenes and displayed lower activity, except Pectis odorata oil, which presented limonene (50.2%), neral (27.2%), and geranial (23.6%) as the major compounds and an IC50 value of 39.6 μg/mL. In addition, the essential oils of Artemisia mendozana, rich in camphor (22.4%), artemisole (11.7%), and artemisia alcohol (10.8%); Gailardia megapotamica composed of β-pinene (35.5%), spathulenol (10.7%), and germacrene D (6.8%); and Heterothalamus alienus characterized by β-pinene (35.5%), spathulenol (10.7%), and germacrene D (6.8%), showed an average IC50 value of 130.63 μg/mL.\nYellow fever (YF), caused by yellow fever virus (YFV), has historically been considered one of the most dangerous infectious diseases. YFV is transmitted to humans via mosquitoes of the Haemogogus, Sabethes, and Aedes genera. Annually, there are approximately 80,000–200,000 YFV cases worldwide, with a case fatality rate (CFR) ranging from 20–60% [93,94]. Essential oils of Lippia species and their main compounds have been tested against yellow fever virus (YFV) in Vero cells. The oil of Lippia origanoides showed carvacrol (44.0%), thymol (15.0%), and γ-terpinene (10.0%) as the main compounds and displayed 100% inhibition at a concentration of 11.1 μg/mL [43]. However, in the same study, the oil of L. alba displayed 100% inhibition at a concentration of 100.0 μg/mL. The major compounds were carvone (51.0%), limonene (33.0%), and bicyclosesquiphellandrene (7.0%). The essential oil of L. alba with a similar chemical composition, carvone (39.7%), limonene (30.6%), and bicyclosesquiphellandrene (8.9%), displayed an IC50 value of 4.3 μg/mL against YFV when tested in Vero cells using the MTT assay [62]. The essential oil of L. citriodora, dominated by geranial (18.9%), neral (15.6%), and limonene (10.7%), did not display a statistical difference in comparison to citral, with IC50 values of 19.4 and 17.6 μg/mL, respectively [62].\nIn addition to essential oils, several individual essential oil components have been screened for antiviral activity (Table 2).\nBecause of the activities of several essential oils and essential oil components against human pathogenic viruses, we hypothesized that essential oil components may be potentially useful as antiviral agents against SARS-CoV-2. In this work, we carried out a molecular docking analysis of the major components of essential oils that exhibit antiviral activity (Table 1 and Table 2) with known SARS-CoV-2 protein targets."}

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