Activity of THC, CBD, and CBN on Human ACE2 and SARS-CoV1/2 Main Protease to Understand Antiviral Defense Mechanism

Thanet Pitakbut; Gia-Nam Nguyen; Oliver Kayser

doi:10.1055/a-1581-3707

Planta Medica, Table of Contents

Planta Med 2022; 88(12): 1047-1059
DOI: 10.1055/a-1581-3707

Biological and Pharmacological Activity

Original Papers

Activity of THC, CBD, and CBN on Human ACE2 and SARS-CoV1/2 Main Protease to Understand Antiviral Defense Mechanism

Thanet Pitakbut

¹Technical Biochemistry, Faculty of Biochemical and Chemical Engineering, TU Dortmund University, Dortmund, Germany

,

Gia-Nam Nguyen

¹Technical Biochemistry, Faculty of Biochemical and Chemical Engineering, TU Dortmund University, Dortmund, Germany

²MINDbioscience GmbH, Dortmund, Germany

,

Oliver Kayser

¹Technical Biochemistry, Faculty of Biochemical and Chemical Engineering, TU Dortmund University, Dortmund, Germany

› Author Affiliations

Abstract

THC, CBD, and CBN were reported as promising candidates against SARS-CoV2 infection, but the mechanism of action of these three cannabinoids is not understood. This study aims to determine the mechanism of action of THC, CBD, and CBN by selecting two essential targets that directly affect the coronavirus infections as viral main proteases and human angiotensin-converting enzyme2. Tested THC and CBD presented a dual-action action against both selected targets. Only CBD acted as a potent viral main protease inhibitor at the IC₅₀ value of 1.86 ± 0.04 µM and exhibited only moderate activity against human angiotensin-converting enzyme2 at the IC₅₀ value of 14.65 ± 0.47 µM. THC acted as a moderate inhibitor against both viral main protease and human angiotensin-converting enzymes2 at the IC₅₀ value of 16.23 ± 1.71 µM and 11.47 ± 3.60 µM, respectively. Here, we discuss cannabinoid-associated antiviral activity mechanisms based on in silico docking studies and in vitro receptor binding studies.

Key words

Δ-9-Tetrahydrocannabinol - Cannabidiol - Cannabinol - coronavirus main protease1/2 - human angiotensin-converting enzyme2 - Cannabis sativa - Cannabaceae

Full Text

References

References
1 Ben-Shabat S, Yarmolinsky L, Porat D, Dahan A. Antiviral effect of phytochemicals from medicinal plants: Applications and drug delivery strategies. Drug Deliv Transl Res 2020; 10: 354-367
2 Watanabe K. Drug-repositioning approach for the discovery of anti-influenza virus activity of Japanese herbal (Kampo) medicines in vitro: Potent high activity of Daio-Kanzo-To. Evid Based Complement Alternat Med 2018; 2018: 6058181
3 Rajasekaran D, Palombo EA, Chia Yeo T, Lim Siok Ley D, Lee Tu C, Malherbe F, Grollo L. Identification of traditional medicinal plant extracts with novel anti-influenza activity. PLoS One 2013; 8: e79293
4 Parvez MK, Tabish Rehman M, Alam P, Al-Dosari MS, Alqasoumi SI, Alajmi MF. Plant-derived antiviral drugs as novel hepatitis B virus inhibitors: Cell culture and molecular docking study. Saudi Pharm J 2019; 27: 389-400
5 Jahan I, Onay A. Potentials of plant-based substance to inhabit and probable cure for the COVID-19. Turk J Biol 2020; 44: 228-241
6 Boukhatem MN, Setzer WN. Aromatic herbs, medicinal plant-derived essential oils, and phytochemical extracts as potential therapies for Coronaviruses: Future perspectives. Plants 2020; 9: 800
7 Wink M. Potential of DNA intercalating alkaloids and other plant secondary metabolites against SARS-CoV-2 causing COVID-19. Diversity 2020; 12: 175
8 Martinez JP, Sasse F, Brönstrup M, Diez J, Meyerhans A. Antiviral drug discovery: Broad-spectrum drugs from nature. Nat Prod Rep 2015; 32: 29-48
9 Hensel A, Bauer R, Heinrich M, Spiegler V, Kayser O, Hempel G, Kraft K. Challenges at the time of COVID-19: Opportunities and innovations in antivirals from nature. Planta Med 2020; 86: 659-664
10 De Clercq E, Li G. Approved antiviral drugs over the past 50 years. Clin Microbiol Rev 2016; 29: 695-747
11 Wang Z, Yang L. Turning the tide: Natural products and natural-product-inspired chemicals as potential counters to SARS-CoV-2 infection. Front Pharmacol 2020; 11: 1013
12 Ni D, Ho DH, Vijjeswarapu M, Felix E, Rhea PR, Newman RA. Metabolism of homoharringtonine, a cytotoxic component of the evergreen plant Cephalotaxus harringtonia. J Exp Ther Oncol 2003; 3: 47-52
13 Abdelkafi H, Nay B. Natural products from Cephalotaxus sp.: chemical diversity and synthetic aspects. Nat Prod Rep 2012; 29: 845-869
14 Kaur P, Thiruchelvan M, Lee RCH, Chen H, Chen KC, Ng ML, Chu JJ. Inhibition of chikungunya virus replication by harringtonine, a novel antiviral that suppresses viral protein expression. Antimicrob Agents Chemother 2013; 57: 155
15 Dong HJ, Wang ZH, Meng W, Li CC, Hu YX, Zhou L, Wang XJ. The natural compound homoharringtonine presents broad antiviral activity in vitro and in vivo . Viruses 2018; 10: 601
16 Kim JE, Song YJ. Anti-varicella-zoster virus activity of cephalotaxine esters in vitro . J Microbiol 2019; 57: 74-79
17 Choy KT, Wong AYL, Kaewpreedee P, Sia SF, Chen D, Hui KPY, Chu DKW, Chan MCW, Cheung PP, Huang X, Peiris M, Yen HL. Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro . Antiviral Res 2020; 178: 104786
18 Bleasel MD, Peterson GM. Emetine, Ipecac, Ipecac alkaloids and analogues as potential antiviral agents for Coronaviruses. Pharmaceuticals 2020; 13: 51
19 Rosales-López C, Muñoz-Arrieta R, Abdelnour-Esquivel A. Emetine and cephaeline content in plants of Psychotria ipecacuanha in Costa Rica. Rev Colomb Quim 2020; 49: 18-22
20 Yang S, Xu M, Lee EM, Gorshkov K, Shiryaev SA, He S, Sun W, Cheng YS, Hu X, Tharappel AM, Lu B, Pinto A, Farhy C, Huang CT, Zhang Z, Zhu W, Wu Y, Zhou Y, Song G, Zhu H, Shamim K, Martínez-Romero C, García-Sastre A, Preston RA, Jayaweera DT, Huang R, Huang W, Xia M, Simeonov A, Ming G, Qiu X, Terskikh AV, Tang H, Song H, Zheng W. Emetine inhibits Zika and Ebola virus infections through two molecular mechanisms: Inhibiting viral replication and decreasing viral entry. Cell Discov 2018; 4: 31
21 Wang A, Sun Y, Liu Q, Wu H, Liu J, He J, Yu J, Chen QQ, Ge Y, Zhang Z, Hu C, Chen C, Qi Z, Zou F, Liu F, Hu J, Zhao M, Huang T, Wang B, Wang L, Wang W, Wang W, Ren T, Liu J, Sun Y, Fan S, Wu Q, Liang C, Sun L, Su B, Wei W, Liu Q. Low dose of emetine as potential anti-SARS-CoV-2 virus therapy: Preclinical in vitro inhibition and in vivo pharmacokinetic evidences. Mol biomed 2020; 1: 14
22 Ribaudo G, Coghi P, Yang LJ, Ng JPL, Mastinu A, Memo M, Wong VKW, Gianoncelli A. Computational and experimental insights on the interaction of artemisinin, dihydroartemisinin and chloroquine with SARS-CoV-2 spike protein receptor-binding domain (RBD). Nat Prod Res 2021;
23 El Biali M, Broers B, Besson M, Demeules J. Cannabinoids and COVID-19. Med Cannabis Cannabinoids 2020; 3: 111-115
24 Hill KP. Cannabinoids and the Coronavirus. Cannabis Cannabinoid Res 2020; 5: 118-120
25 Esposito G, Pesce M, Seguella L, Sanseverino W, Lu J, Corpetti C, Sarnelli G. The potential of cannabidiol in the COVID-19 pandemic. Br J Pharmacol 2020; 177: 4967-4970
26 Onaivi ES, Sharma V. Cannabis for COVID-19: can cannabinoids quell the cytokine storm?. Future Sci OA 2020; 6: FSO625
27 Dzobo K, Chiririwa H, Dandara C, Dzobo W. Coronavirus disease-2019 treatment strategies targeting interleukin-6 signaling and herbal medicine. OMICS 2020; 25: 13-22
28 Wang B, Kovalchuk A, Li D, Rodriguez-Juarez R, Ilnytskyy Y, Kovalchuk I, Kovalchuk O. In search of preventive strategies: Novel high-CBD Cannabis sativa extracts modulate ACE2 expression in COVID-19 gateway tissues. Aging (Albany NY) 2020; 12: 22425-22444
29 Raj V, Park JG, Cho KH, Choi P, Kim T, Ham J, Lee J. Assessment of antiviral potencies of cannabinoids against SARS-CoV-2 using computational and in vitro approaches. Int J Biol Macromol 2021; 168: 474-485
30 Tallei TE, Tumilaar SG, Niode NJ, Fatimawali. Kepel BJ, Idroes R, Effendi Y, Sakib SA, Emran TB. Potential of plant bioactive compounds as SARS-CoV-2 Main Protease (M^pro) and Spike (S) glycoprotein inhibitors: A molecular docking study. Scientifica (Cairo) 2020; 2020: 6307457
31 Schulz U, Freitag M, Schmidt K, Witetschek M, Polzin M, Morgenstern O. Synthesis and structure elucidation of 2,3,5,6,7,8-hexahydro-1 H-[1,2,4]triazolo[1,2-a]pyridazine-1-thione, 3,3-disubstituted and 2-substituted derivatives and evaluation of their inhibitory activity against inducible nitric oxide synthase. Pharmazie 2014; 69: 731-744
32 Aleo MF, Bettoni F, Boniotti J, Morandini F, Giuliani R, Steimberg N, Apostoli P, Mazzoleni G. A comparative in vitro study of the toxic potency of five inorganic lead compounds on a rat liver epithelial cell line (REL). Toxicol In Vitro 2006; 20: 874-881
33 Chitranshi N, Gupta VK, Rajput R, Godinez A, Pushpitha K, Shen T, Mirzaei M, You Y, Basavarajappa D, Gupta V, Graham SL. Evolving geographic diversity in SARS-CoV2 and in silico analysis of replicating enzyme 3 CL^pro targeting repurposed drug candidates. J Transl Med 2020; 18: 278
34 Hevener KE, Zhao W, Ball DM, Babaoglu K, Qi J, White SW, Lee RE. Validation of molecular docking programs for virtual screening against dihydropteroate synthase. J Chem Inf Model 2009; 49: 444-460
35 Pagadala NS, Syed K, Tuszynski J. Software for molecular docking: A review. Biophys Rev 2017; 9: 91-102
36 Fu L, Ye F, Feng Y, Yu F, Wang Q, Wu Y, Zhao C, Sun H, Huang B, Niu P, Song H, Shi Y, Li X, Tan W, Qi J, Gao GF. Both Boceprevir and GC376 efficaciously inhibit SARS-CoV-2 by targeting its main protease. Nat Commun 2020; 11: 4417
37 Böhme T, Simpson CD, Müllen K, Rabe JP. Current–voltage characteristics of a homologous series of polycyclic aromatic hydrocarbons. Chem Eur J 2007; 13: 7349-7357
38 Tay MZ, Poh CM, Rénia L, MacAry PA, Ng LFP. The trinity of COVID-19: immunity, inflammation and intervention. Nat Rev Immunol 2020; 20: 363-374
39 Rossi F, Tortora C, Argenziano M, Di Paola A, Punzo F. Cannabinoid receptor type 2: A possible target in SARS-CoV-2 (CoV-19) infection?. Int J Mol Sci 2020; 21: 3809
40 Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, Schiergens TS, Herrler G, Wu NH, Nitsche A, Müller MA, Drosten C, Pöhlmann S. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and Is blocked by a clinically proven protease inhibitor. Cell 2020; 181: 271-280.e8
41 Jin Z, Du X, Xu Y, Deng Y, Liu M, Zhao Y, Zhang B, Li X, Zhang L, Peng C, Duan Y, Yu J, Wang L, Yang K, Liu F, Jiang R, Yang X, You T, Liu X, Yang X, Bai F, Liu H, Liu X, Guddat LW, Xu W, Xiao G, Qin C, Shi Z, Jiang H, Rao Z, Yang H. Structure of M^pro from SARS-CoV-2 and discovery of its inhibitors. Nature 2020; 582: 289-293
42 Choi BW, Lee HS, Shin HC, Lee BH. Multifunctional activity of polyphenolic compounds associated with a potential for alzheimerʼs disease therapy from Ecklonia cava. Phytother Res 2015; 29: 549-553
43 Rana M, Pareek A, Bhardwaj S, Arya G, Nimesh S, Arya H, Bhatt TK, Yaragorla S, Sharma AK. Aryldiazoquinoline based multifunctional small molecules for modulating Aβ₄₂ aggregation and cholinesterase activity related to Alzheimerʼs disease. RSC Adv 2020; 10: 28827-28837
44 Koch N, Jennotte O, Gasparrini Y, Vandenbroucke F, Lechanteur A, Evrard B. Cannabidiol aqueous solubility enhancement: Comparison of three amorphous formulations strategies using different type of polymers. Int J Pharm 2020; 589: 119812
45 Millar SA, Maguire RF, Yates AS, OʼSullivan SE. Towards better delivery of Cannabidiol (CBD). Pharmaceuticals (Basel) 2020; 13: 219
46 Towler P, Staker B, Prasad SG, Menon S, Tang J, Parsons T, Ryan D, Fisher M, Williams D, Dales NA, Patane MA, Pantoliano MW. ACE2 X-ray structures reveal a large hinge-bending motion important for inhibitor binding and catalysis. J Biol Chem 2004; 279: 17996-18007
47 Wang Q, Zhang Y, Wu L, Niu S, Song C, Zhang Z, Lu G, Qiao C, Hu Y, Yuen KY, Wang Q, Zhou H, Yan J, Qi J. Structural and functional basis of SARS-CoV-2 entry by using human ACE2. Cell 2020; 181: 894-904.e9
48 Malin JJ, Suárez I, Priesner V, Fätkenheuer G, Rybniker J. Remdesivir against COVID-19 and other viral diseases. Clin Microbiol Rev 2020; 34: e00162-20
49 Gordon CJ, Tchesnokov EP, Woolner E, Perry JK, Feng JY, Porter DP, Götte M. Remdesivir is a direct-acting antiviral that inhibits RNA-dependent RNA polymerase from severe acute respiratory syndrome coronavirus 2 with high potency. J Biol Chem 2020; 295: 6785-6797
50 Maciorowski D, Idrissi SZE, Gupta Y, Medernach BJ, Burns MB, Becker DP, Durvasula R, Kempaiah P. A review of the preclinical and clinical efficacy of remdesivir, hydroxychloroquine, and lopinavir-ritonavir treatments against COVID-19. SLAS Discov 2020; 25: 1108-1122
51 Carr NT. Using Microsoft Excel^® to calculate descriptive statistics and create graphs. Lang Assess Q 2008; 5: 43-62
52 Papautsky EL, Hamlish T. Patient-reported treatment delays in breast cancer care during the COVID-19 pandemic. Breast Cancer Res Treat 2020; 184: 249-254
53 Becker RC. COVID-19 and its sequelae: a platform for optimal patient care, discovery and training. J Thromb Thrombolysis 2021;
54 Jasper EE, Ajibola VO, Onwuka JC. Nonlinear regression analysis of the sorption of crystal violet and methylene blue from aqueous solutions onto an agro-waste derived activated carbon. Appl Water Sci 2020; 10: 132
55 R Core Team. R: A Language and Environment for Statistical Computing. Vienna, Austria: R Foundation for Statistical Computing; 2021. Accessed March 16 2021 at: https://www.R-project.org/
56 R Studio Team. RStudio: Integrated Development Environment for R. Boston, MA: RStudio, PBC; 2021. Accessed March 16, 2021 at: http://www.rstudio.com/
57 Baty F, Ritz C, Charles S, Brutsche M, Flandrois JP, Delignette-Muller ML. A toolbox for nonlinear regression in R: The package nlstools. J Stat Softw 2015; 66: 1-21
58 Zeviani WM. wzRfun: Walmes Zevianiʼs collection of functions. 2019. Accessed March 18, 2021 at: https://github.com/walmes/wzRfun
59 Hanwell MD, Curtis DE, Lonie DC, Vandermeersch T, Zurek E, Hutchison GR. Avogadro: An advanced semantic chemical editor, visualization, and analysis platform. J Cheminformatics 2012; 4: 17
60 Trott O, Olson AJ. AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 2010; 31: 455-461
61 Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, Ferrin TE. UCSF Chimera–A visualization system for exploratory research and analysis. J Comput Chem 2004; 25: 1605-1612
62 Schneider N, Hindle S, Lange G, Klein R, Albrecht J, Briem H, Beyer K, Claußen H, Gastreich M, Lemmen C, Rarey M. Substantial improvements in large-scale redocking and screening using the novel HYDE scoring function. J Comput Aided Mol Des 2012; 26: 701-723
63 Musoev A, Numonov S, You Z, Gao H. Discovery of novel DPP-IV inhibitors as potential candidates for the treatment of type 2 diabetes mellitus predicted by 3D QSAR Pharmacophore models, molecular docking and de novo evolution. Molecules 2019; 24: 2870
64 Gurung AB, Ali MA, Lee J, Farah MA, Al-Anazi KM. Unravelling lead antiviral phytochemicals for the inhibition of SARS-CoV-2 M^pro enzyme through in silico approach. Life Sci 2020; 255: 117831
65 Ramírez D, Caballero J. Is it reliable to take the molecular docking top scoring position as the best solution without considering available structural data?. Molecules 2018; 23: 1038
66 Velázquez-Libera JL, Murillo-López JA, de la Torre AF, Caballero J. Structural requirements of N-alpha-Mercaptoacetyl Dipeptide (NAMdP) inhibitors of pseudomonas aeruginosa virulence factor LasB: 3D-QSAR, molecular docking, and interaction fingerprint studies. Int J Mol Sci 2019; 20: 6133
67 Biovia DS. Discovery Studio Visualizer. San Diego, CA, USA: Dassault Systèmes; 2017: 936

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