Nigella sativa L. and COVID-19: A Glance at The Anti-COVID-19 Chemical Constituents, Clinical Trials, Inventions, and Patent Literature
Abstract
:1. Introduction
2. Materials and Methods
3. N. sativa L.
3.1. Introduction
3.2. Important Biologically Active Chemical Constituents of NS
3.3. Anti-COVID-19 Chemical Constituents of NS
3.4. Anti-COVID-19 Clinical Trials on NS and Its Chemical Constituents
4. Patent Summary
5. Conclusions
6. Discussion and Perspective
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Acknowledgments
Conflicts of Interest
References
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NS Constituent Identified as Anti-COVID-19 | Type of Study | Finding of the Study |
---|---|---|
Caryophyllene oxide, β-bisabolene | In silico | Molecular docking studies (PDB IDs: 6YHU, 6W4B, 6VXS, 6LU7, 7BTF 6LZG) revealed caryophyllene oxide to possess the highest binding affinity towards 3CLpro, NSP3, NSP9, and RdRp molecular targets in COVID-19. ACE-2 binding affinity of β-bisabolene and remdesivir was almost similar [56] |
Dithymoquinone (DTQ) | In silico | The binding affinity (PDB ID: 6VW1) of DTQ on SARS-CoV-2-ACE-2 was better than chloroquine. It was found to be stable at the docked site in molecular dynamics simulation studies [57] |
α-Hederin | In silico | α-Hederin was found to be a better inhibitor of RdRp (PDB ID: 6M71) than DTQ, nigellicine, and nigellidine [58] |
DTQ | In silico | DTQ was found to be active against 3CLpro (PDB ID: 6LU7) and Nsp15 (PDB ID: 6VWW) targets [59] |
α -Hederin, rutin, and nigellamine A2 | In silico | α-Hederin, rutin, and nigellamine A2 were identified as potential inhibitors of SARS-CoV-2 proteins (PDB IDs: 6W9C, 6Y2E, 6M71, 6ZSL, 6W4B, 6VWW, 6M17, and 6VYO) related to RdRp, protease, and helicase [60] |
Nigellidine | In silico and in vivo | Nigellidine showed a good affinity toward COVID-19 Nsp2 and IL1R proteins (PDB IDs: 6LU7, 6VSB, 1ITB, and 1P9M). Nigellidine in vivo study in rats showed antioxidant, hepato-protective, and anti-inflammatory activities [61] |
α-Hederin | In silico | NS chemical constituents such as α-hederin, stigmasterol glucoside, nigellidine-4-O-sulfite, nigellidine, sterol-3-β-D-glucoside, DTQ, β-sitosterol were identified as potential inhibitors of main protease (Mpro) (PDB IDs: 6LU7). Nigllimine, nigellimine N-oxide, carvacrol, TQ, THQ, thymol, anthole, etc., showed weaker binding affinity than remdesivir, lopinavir, and nelfinavir. α-Hederin was identified as the most promising anti-COVID agent [62] |
α-Hederin, THQ, and TQ | In silico | In molecular docking studies, α-hederin, THQ, and TQ were found to be efficiently binding to ACE-2 (PDB ID: 1R4L) of SARS-CoV-2 [63] |
Nigellone | In silico | Nigellone (DTQ) upon molecular docking studies with four COVID-19 protein targets (spike glycoprotein, 3CLpro/Mpro (PDB ID: 6LU7), human ACE-2) was observed to bind more strongly than carvacrol, nigellicine, nigellidine, TQ, THQ, and thymol. Its binding affinity on other viral proteins (PDB IDs: 6LU7, 6VSB, and 6VX) was better than remdesivir and hydroxychloroquine [64]. This study also advocated further in vitro experiments to establish Nigellone as an anti-COVID-19 lead compound |
Nigellidine | In silico | Nigellidine was exposed to prevent SARS-CoV-2 NSP3 replication/transcription. It also blocked the pro-inflammatory cytokines TNF R1 and TNF R2 and Fas-induced apoptotic death [55] |
DTQ and THQ | In vitro | Cytotoxicity of DTQ and THQ was tested in VERO-E6 cells by MTT assay. HTQ presented anti-SARS-CoV-2 action at non-cytotoxic nanomolar concentration (IC50 = 23.15 ng/mL) while DTQ showed an IC50 of 275.2 ng/mL [65] |
TQ | In Silico and in vitro | TQ is bound strongly to ACE-2 of SARS-CoV-2 (PDB ID: 6VW1). In vitro results showed it to inhibit SARS-CoV-2 pseudo particles infecting HEK293-ACE2 cells with IC50 of 4.999 μM and CC50 of 35.100 μM; SI = 7.02) [66] |
Summary of the Title (Intervention) | Primary Purpose (Phase; Number of Enrollments; Status; Results) | NCT Number (Allocation; Intervention Model; Completion Date) | Sponsor (Location of the Clinical Trial) | Primary Outcomes/Conclusion |
---|---|---|---|---|
NS in COVID-19 (Oral soft gel capsule containing 500 mg NSO two times a day for 10 days) | Treatment (2; 183; Completed; Available) | NCT04401202 (Randomized; Parallel Assignment; 31 December 2020) | King Abdulaziz University (Saudi Arabi) | The dietary supplement helped the faster recovery of COVID-19 patients |
Safety and efficacy of NSO against COVID-19 (Six 500 mg capsules of NSO per day for 14 days) | Treatment (2; 60; Recruiting; Not available) | NCT04914377 (Randomized; Parallel Assignment; November 2021) | Novatek Pharmaceuticals (United States) | The reduction in the COVID-19 signs and symptoms |
Effectiveness of NSO to treat COVID-19 (One capsule of NS every 2 h for the first 3 days followed by one capsule three times a day for 12 days. The dose of NSO is not mentioned) | Treatment (1; 500; Completed; Not available) | NCT04914767 (Randomized; Parallel Assignment; 31 December 2021) | Sahloul University Hospital (Tunisia) | Rate of death, readmission, and oxygen supplementation among high-risk COVID-19 patients |
Honey and NS seeds for COVID-19 treatment (Honey 1 g/kg daily + NS seed capsule, 80 mg/kg daily for 14 days) | Treatment (3; 313; Completed; Not available) | NCT04347382 (Randomized; Parallel Assignment; 30 August 2020) | Sohaib Ashraf and Sheikh Zayed Federal Postgraduate Medical Institute (Pakistan) | Days needed to obtain a negative COVID-19 PCR of a COVID-19 positive patient |
Efficacy of NS versus vitamin D3 against COVID-19 (NS capsule, 900 mg two times a day for 14 days) | Treatment (Not Applicable; 100; Recruiting; Not available) | NCT04981743 (Randomized; Parallel Assignment; 30 December 2021) | Ain Shams University (Egypt) | The safety and efficacy of NS versus vitamin D3 against COVID-19 will be evaluated and recorded utilizing COVID-19 signs and symptoms (fever, runny nose, fatigue, cough, sore throat, and headache) |
Impact of the composition of NSO and Omega 3 on the immunity of COVID-19 patient (1g Omega 3 and 1g NSO containing 3% TQ for 14 days) | Treatment (2 & 3; Recruiting; Not available) | NCT04553705 (Randomized; Sequential Assignment; 4 December 2020) | Beni-Suef University, Maternity and Children Hospital (Makkah), and University of Arizona (Saudi Arabia) | The recovery rate from COVID-19 positive to COVID-19 negative |
NS for the prevention of influenza syndrome (One capsule of NS per day for 21 days followed by weekly follow-up for COVID-19 checking. The dose is not mentioned) | Prevention (Not applicable; 500; Completed; Not available) | NCT04989101 (Randomized; Parallel Assignment; 31 August 2021) | Sahloul University Hospital (Tunisia) | SARS-CoV-19 infection |
Honey and NS seeds for COVID-19 prophylaxis (Honey 0.5 g/kg daily + NS seeds 40 mg/kg daily for 14 days) | Prevention (2 & 3; 1000; Recruiting; Not available) | NCT04767087 (Randomized; Parallel Assignment; 15 April 2022) | Sohaib Ashraf and Sheikh Zayed Federal Postgraduate Medical Institute (Pakistan) | The combination of honey and NS improved the symptoms, viral clearance, and mortality among COVID-19 patients |
Patent/Patent Application Number (Applicant/Assignee; Publication Date; Priority Country) | Status (Family Members; International Patent Classification) | Summary of the Claimed Invention |
---|---|---|
US11229674B1 (Therapeutic Solutions International; 25 January 2022; United States) | Patented case (None; A61K36/31, A61K36/45, A61K36/71, A61K36/82, A61P29/00) | A quadramune composition comprising 100–200 ug of green tea extract (epigallocatechin-3-gallate), 100–200 ug of NS extract (TQ), 100–200 ug of broccoli extract (sulforaphane), and 50-100 ug of blueberry extract (pterostilbene) to treat COVID-19 patient. This composition is said to possess anti-inflammatory activity and improves immunity by inhibiting the expression of indoleamine 2,3-dioxygenase. However, no clinical or in vitro analysis data have been provided in support of the claimed method of treatment [72]. |
US20210338763A1 (Therapeutic Solutions International; 4 November 2021; United States) | Under examination (None; A61K31/09, A61K31/122, A61K31/26, A61K31/353, A61K36/31, A61K36/45, A61K36/71, A61K36/82) | It claims a nutraceutical composition similar to US11229674B1 [72] comprising NS, green tea, blueberry, and broccoli for treating or preventing complications linked with the infection of SARS-CoV-2. The composition is claimed to reduce the expression of inflammatory markers in the human body. No example has been provided in the specification to support the claimed invention, but inventors tried to justify their claims based on prior studies [73]. |
WO2022009236A1 (Mozhdeh Haddadi and Mahdyar Taghdisi Hadi Pour; 13 January 2022; Iran) | No national phase entry (A61K36/00) | It claims four types of compositions of NS (capsule/tablet) for the treatment of COVID-19 (10 days course) containing different dry and powdered herbs. First composition for patients < 3 years comprised of NS and Terminalia chebula (TC). Second composition for patients of 3–7 years comprised of NS, Apple seed, and TC. Third composition for patients 7–15 years comprised of NS, Peganum harmala (PH), and TC. Fourth composition for patients >15 years NS, PH, Apple seed, and TC. This document does not deliver any experimental proof (in vitro, in vivo, or clinical) for the claimed treatment [74]. |
US20220000958A1 (Covimmune Pharma; 6 January 2022; United States) | Under examination (A61K36/71, A61P31/14) | A biologically active immunostimulant extract obtained by the extraction of NS plant, NS seed, or its oil with aqueous ethanoic acid (vinegar) for the treatment of COVID-19. The patent application provides a pictorial mechanism of action of the NS extract to treat COVID-19. However, no anti-COVID-19 activity data (in vitro, in vivo, and clinical) of the extract have been exemplified [75]. |
TR2020004046A2 (Alravvi, Omar, Turk; 21 April 2020; Turkey) | Granted patent (Not available online) | An antiviral herbal composition comprising NSO (60–80%), olive oil (10–20%), and clove oil (1–5%) for treating COVID-19. The complete document was not available for analyzing the examples [76]. |
WO2021205196A1 (Muhammad Taliah; 14 October 2021; International Bureau of The World Intellectual Property Organization) | No national phase entry (WO2021205196A4; A61K36/19, A61K36/38, A61K36/48, A61K36/70, A61P31/14) | A composition comprising NS seed (anti-SARS-CoV-2) and Saussurea lappa root (anti-SARS-CoV-2) for treating/preventing COVID-19. The optional components of the composition include, Astragalus membranaceus root (immunomodulator/reduces viral load), Paeonia lactiflora root (anti-inflammatory/immunomodulator), Radix bupleuri root (anti-inflammatory), Nelumbo nucifera seed (antioxidant), Angelica archangelica root (antioxidant), Citrus sinensis peel (antioxidant), Rosa canina fruit (antioxidant), Vaccinium angustifolium fruit (antioxidant), Polygonum cuspidatum root (antioxidant/antiviral), Ocimum sanctum leaf (antiviral), Andrographis paniculate aerial parts (antiviral), Artemisia vulgaris leaf (autophagy inducer), Zingiber officinale root (autophagy inducer), Glycyrrhiza glabra root (antimutagenic), and Panax ginseng root (reduces lethargy and fatigue associated with COVID-19). This patent application provides a protocol for the clinical study of the claimed composition but is silent about its data [77]. |
US2022023237A1 (Therapeutic Solutions International; 27 January 2022; United States) | Under examination (None; A23L33/105, A61K31/155, A61K36/31, A61K36/45, A61K36/82) | A synergistic composition to treat/prevent COVID-19 comprising metformin, Green Tea extract (epigallocatechin-3-gallate), blueberry extract (pterostilebene), NS extract (TQ), and broccoli extract (sulforaphane). The in vivo activity data demonstrated that the claimed composition enhanced type 2 monocytes, IL-10 (anti-inflammatory protein), and HGF-1 (regenerative protein). It also reduced lung injury, and IL-17 (inflammatory protein). However, no specific data have been provided against SARS-CoV-2 or COVID-19 treatment [78]. |
US2022031793A1 (Therapeutic Solutions International; 3 February 2022; United States) | Under examination (None; A61K31/09, A61K31/122, A61K31/26, A61K31/353, A61K36/31, A61K36/45, A61K36/71, A61K36/82) | A method of protecting against neurological damage due to COVID-19 utilizing a composition comprising green tea extract (epigallocatechin-3-gallate), blueberry extract (pterostilbene), NS extract (TQ), and broccoli extract (sulforaphane) [79]. |
US2022040248A1 (Therapeutic Solutions International; 10 February 2022; United States) | Under examination (None; A61K31/09, A61K31/122, A61K31/26, A61K31/353, A61K36/31, A61K36/45, A61K36/71, A61K36/82, A61P25/28) | A method of treating inflammation associated with neurological damage due to COVID-19 utilizing a composition comprising green tea extract (epigallocatechin-3-gallate), blueberry extract (pterostilbene), NS extract (TQ), and broccoli extract (sulforaphane) [80]. |
WO2021186453A1 (Alkalay Rachel; 23 September 2021; United States) | No national phase entry (WO2021186454A1, WO2021186455A1, WO2021186456A1; A61K31/05, A61K36/25, A61K36/258, A61K36/324, A61K36/424, A61K36/53, A61K36/537, A61P11/00, A61P31/14) | A method of preventing or treating SARS-CoV-2 infection using a composition containing oregano oil (1), thyme oil (2), NSO (3), sumac oil (4), sesame oil (5), olibanum oil (6). Different combinations of these oils were made as combination A (1+2+3), combination B (1+2+3+4), combination C (1+2+3+4+5), and combination D (1+2+3+4+5+6). The in vitro analysis of these combinations demonstrated that these combinations digested the S-1 and S-2 subunits of the spike protein of SARS-CoV-2 and attenuated it. The clinical trial in a patient showed that the combination-A relieved sore throat and cough in 24 and 40 h, respectively [81]. |
WO2021186454A1 (Alkalay Rachel; 23 September 2021; United States) | No national phase entry (WO2021186453A1, WO2021186455A1, WO2021186456A1; A61K31/05, A61K36/25, A61K36/258, A61K36/324, A61K36/424, A61K36/53, A61K36/537, A61P11/00, A61P31/14) | This is a family member of WO2021186453A1 [81] with similar data. It claims a method of lowering the infectivity of a non-malignant respiratory disease virus using a combination of NS along with other herbs as mentioned in WO2021186453A1 [81,82]. |
WO2021186455A1 (Alkalay Rachel; 23 September 2021; United State) | No national phase entry (WO2021186453A1, WO2021186454A1, WO2021186456A1; A61K31/05, A61K36/25, A61K36/258, A61K36/324, A61K36/424, A61K36/53, A61K36/537, A61P31/12, C07K14/47) | This is a family member of WO2021186453A1 [81] with similar data. It claims an anti-inflammatory composition of NS along with other herbs as mentioned in WO2021186453A1 [81,83]. |
WO2021186456A1 (Alkalay Rachel; 23 September 2021; United States) | No national phase entry (WO2021186453A1, WO2021186454A1, WO2021186455A1; A61K31/045, A61K31/05, A61K31/121, A61K31/198, A61K31/352, A61K36/258, A61K36/424, A61K38/48, A61P35/00) | This is a family member of WO2021186453A1 [81] with similar data. It claims the antiviral composition of NS along with other herbs as mentioned in WO2021186453A1 [81]. However, it is silent about the antiviral activity against SARS-CoV-2 [81,84]. |
WO2021160982A1 (Nasaleze Patents Limited; 19 August 2021; United Kingdom) | No national phase entry (None; A61K31/685, A61K36/8962, A61K47/38, A61K47/46, A61K9/00, A61K9/14, A61P31/12) | A homogenized powdered composition consisting of hydroxypropyl methylcellulose particles, at least one signaling agent (menthol, strawberry, mint, spearmint, peppermint, eucalyptus, lavender, and citrus), and optionally one or more biologically active agents like NS. This document does not furnish any rationale for using NS in the description part [85]. |
WO2021216749A1 (Hoag George Edward and Salerno John; 28 October 2021; United States) | No national phase entry (None; A61K31/015, A61K31/045, A61K31/12, A61K31/35, A61K9/00, A61P31/04, A61P31/12) | A liquid pharmaceutical composition for inhalation to prevent/treat infectious diseases (COVID-19) containing a plant extract comprising one or more Transient Receptor Potential Cation Channel, Subfamily A, member 1 (TRPA1) antagonist (1,8-cineole), one or more plant extract antibacterial compound (b-caryophyllene), one or more plant extract antiviral compounds (TQ), and one or more plant extract antioxidants (berberine). This patent application does not exemplify the anti-SARS-CoV-2 activity data of the claimed composition [86]. |
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Imran, M.; Khan, S.A.; Abida; Alshammari, M.K.; Alkhaldi, S.M.; Alshammari, F.N.; Kamal, M.; Alam, O.; Asdaq, S.M.B.; Alzahrani, A.K.; et al. Nigella sativa L. and COVID-19: A Glance at The Anti-COVID-19 Chemical Constituents, Clinical Trials, Inventions, and Patent Literature. Molecules 2022, 27, 2750. https://doi.org/10.3390/molecules27092750
Imran M, Khan SA, Abida, Alshammari MK, Alkhaldi SM, Alshammari FN, Kamal M, Alam O, Asdaq SMB, Alzahrani AK, et al. Nigella sativa L. and COVID-19: A Glance at The Anti-COVID-19 Chemical Constituents, Clinical Trials, Inventions, and Patent Literature. Molecules. 2022; 27(9):2750. https://doi.org/10.3390/molecules27092750
Chicago/Turabian StyleImran, Mohd, Shah Alam Khan, Abida, Mohammed Kanan Alshammari, Saif M. Alkhaldi, Fayez Nafea Alshammari, Mehnaz Kamal, Ozair Alam, Syed Mohammed Basheeruddin Asdaq, A. Khuzaim Alzahrani, and et al. 2022. "Nigella sativa L. and COVID-19: A Glance at The Anti-COVID-19 Chemical Constituents, Clinical Trials, Inventions, and Patent Literature" Molecules 27, no. 9: 2750. https://doi.org/10.3390/molecules27092750
APA StyleImran, M., Khan, S. A., Abida, Alshammari, M. K., Alkhaldi, S. M., Alshammari, F. N., Kamal, M., Alam, O., Asdaq, S. M. B., Alzahrani, A. K., & Jomah, S. (2022). Nigella sativa L. and COVID-19: A Glance at The Anti-COVID-19 Chemical Constituents, Clinical Trials, Inventions, and Patent Literature. Molecules, 27(9), 2750. https://doi.org/10.3390/molecules27092750