806
Views
2
CrossRef citations to date
0
Altmetric
Research Paper

The hope and hype of ellagic acid and urolithins as ligands of SARS-CoV-2 Nsp5 and inhibitors of viral replication

, , , , , , , , , , & show all
Article: 2251721 | Received 17 Jun 2023, Accepted 19 Aug 2023, Published online: 28 Aug 2023

References

  • Galea S, Abdalla SM. COVID-19 pandemic, unemployment, and civil unrest: underlying deep racial and socioeconomic divides. JAMA. 2020;324(3):227–228.
  • Rudrapal M, Khairnar SJ, Borse LB, Jadhav AG. Coronavirus disease-2019 (COVID-19): an updated review. Drug Res. 2020;70(9):389–400.
  • Paul E. Address in PATHOLOGY ON CHEMOTHERAPEUTICS. Lancet. 1913;182(4694):445–451.
  • de Wit E, van Doremalen N, Falzarano D, Munster VJ. SARS and MERS: recent insights into emerging coronaviruses. Nat Rev Microbiol. 2016;14(8):523–534.
  • Muramatsu T, Takemoto C, Kim Y-T, Wang H, Nishii W, Terada T, Shirouzu M, Yokoyama S. SARS-CoV 3CL protease cleaves its C-terminal autoprocessing site by novel subsite cooperativity. Proc Natl Acad Sci USA. 2016;113(46):12997–13002.
  • Yang H, Xie W, Xue X, Yang K, Ma J, Liang W, Zhao Q, Zhou Z, Pei D, Ziebuhr J, et al. Design of wide-spectrum inhibitors targeting coronavirus main proteases. PLOS Biol. 2005;3(10):e324.
  • Yang H, Bartlam M, Rao Z. Drug design targeting the main protease, the achilles heel of coronaviruses. Curr Pharm Des. 2006;12(35):4573–4590.
  • Zhang L, Lin D, Sun X, Curth U, Drosten C, Sauerhering L, Becker S, Rox K, Hilgenfeld R. Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors. Science. 2020;368(6489):409–412.
  • Jin Z, Du X, Xu Y, Deng Y, Liu M, Zhao Y, Zhang B, Li X, Zhang L, Peng C, et al. Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors. Nature. 2020;582(7811):289–293.
  • Silvestrini L, Belhaj N, Comez L, Gerelli Y, Lauria A, Libera V, Mariani P, Marzullo P, Ortore MG, Palumbo Piccionello A, et al. The dimer-monomer equilibrium of SARS-CoV-2 main protease is affected by small molecule inhibitors. Sci Rep. 2021;11(1):9283.
  • Paciaroni A, Libera V, Ripanti F, Orecchini A, Petrillo C, Francisci D, Schiaroli E, Sabbatini S, Gidari A, Bianconi E, et al. Stabilization of the dimeric state of SARS-CoV-2 main protease by GC376 and nirmatrelvir. Int J Mol Sci. 2023;24(7):6062.
  • Liu Y, Liang C, Xin L, Ren X, Tian L, Ju X, Li H, Wang Y, Zhao Q, Liu H, et al. The development of coronavirus 3C-Like protease (3CLpro) inhibitors from 2010 to 2020. Eur J Med Chem. 2020;206:112711.
  • Pillaiyar T, Manickam M, Namasivayam V, Hayashi Y, Jung SH. An overview of severe acute respiratory syndrome–coronavirus (SARS-CoV) 3CL protease inhibitors: peptidomimetics and small molecule chemotherapy. J Med Chem. 2016;59(14):6595–6628.
  • Owen DR, Allerton CMN, Anderson AS, Aschenbrenner L, Avery M, Berritt S, Boras B, Cardin RD, Carlo A, Coffman KJ, et al. An oral SARS-CoV-2 Mpro inhibitor clinical candidate for the treatment of COVID-19. Science. 2021;374(6575):1586–1593.
  • Gidari A, Sabbatini S, Schiaroli E, Bastianelli S, Pierucci S, Busti C, Comez L, Libera V, Macchiarulo A, Paciaroni A, et al. The combination of molnupiravir with nirmatrelvir or GC376 has a synergic role in the inhibition of SARS-CoV-2 replication in vitro. Microorganisms. 2022;10(7):1475.
  • Kuzikov M, Costanzi E, Reinshagen J, Esposito F, Vangeel L, Wolf M, Ellinger B, Claussen C, Geisslinger G, Corona A, et al. Identification of inhibitors of SARS-CoV-2 3CL-pro enzymatic activity using a small molecule in vitro repurposing screen. ACS Pharmacol Transl Sci. 2021;4(3):1096–1110.
  • Günther S, Reinke PYA, Fernández-García Y, Lieske J, Lane TJ, Ginn HM, Koua FHM, Ehrt C, Ewert W, Oberthuer D, et al. X-ray screening identifies active site and allosteric inhibitors of SARS-CoV-2 main protease. Science. 2021;372(6542):642–646.
  • Mani JS, Johnson JB, Steel JC, Broszczak DA, Neilsen PM, Walsh KB, Naiker M. Natural product-derived phytochemicals as potential agents against coronaviruses: a review. Virus Res. 2020;284:197989.
  • Nguyen TTH, Woo H-J, Kang H-K, Nguyen VD, Kim Y-M, Kim D-W, Ahn S-A, Xia Y, Kim D. Flavonoid-mediated inhibition of SARS coronavirus 3C-like protease expressed in Pichia pastoris. Biotechnol Lett. 2012;34(5):831–838.
  • Jo S, Kim S, Shin DH, Kim MS. Inhibition of SARS-CoV 3CL protease by flavonoids. J Enzyme Inhib Med Chem. 2020;35(1):145–151.
  • Jo S, Kim H, Kim S, Shin DH, Kim MS. Characteristics of flavonoids as potent MERS-CoV 3C-like protease inhibitors. Chem Biol Drug Des. 2019;94(6):2023–2030.
  • Park J-Y, Ko J-A, Kim DW, Kim YM, Kwon H-J, Jeong HJ, Kim CY, Park KH, Lee WS, Ryu YB, et al. Chalcones isolated from Angelica keiskei inhibit cysteine proteases of SARS-CoV. J Enzyme Inhib Med Chem. 2016;31(1):23–30.
  • Chen L-R, Wang Y-C, Lin YW, Chou S-Y, Chen S-F, Liu LT, Wu Y-T, Kuo C-J, Chen TS-S, Juang S-H, et al. Synthesis and evaluation of isatin derivatives as effective SARS coronavirus 3CL protease inhibitors. Bioorg Med Chem Lett. 2005;15(12):3058–3062.
  • Liu W, Zhu H-M, Niu G-J, Shi E-Z, Chen J, Sun B, Chen W-Q, Zhou H-G, Yang C. Synthesis, modification and docking studies of 5-sulfonyl isatin derivatives as SARS-CoV 3C-like protease inhibitors. Bioorg Med Chem. 2014;22(1):292–302.
  • Ryu YB, Jeong HJ, Kim JH, Kim YM, Park J-Y, Kim D, Nguyen TTH, Park S-J, Chang JS, Park KH, et al. Biflavonoids from Torreya nucifera displaying SARS-CoV 3CLpro inhibition. Bioorg Med Chem. 2010;18(22):7940–7947.
  • Park J-Y, Kim JH, Kim YM, Jeong HJ, Kim DW, Park KH, Kwon H-J, Park S-J, Lee WS, Ryu YB, et al. Tanshinones as selective and slow-binding inhibitors for SARS-CoV cysteine proteases. Bioorg Med Chem. 2012;20(19):5928–5935.
  • Khalifa I, Zhu W, Mohammed HHH, Dutta K, Li C. Tannins inhibit SARS‐CoV‐2 through binding with catalytic dyad residues of 3CLpro : an in silico approach with 19 structural different hydrolysable tannins. J Food Biochem. 2020;44(10):e13432.
  • Li H, Xu F, Liu C, Cai A, Dain JA, Li D, Seeram NP, Cho BP, Ma H. Inhibitory effects and surface plasmon resonance-based binding affinities of dietary hydrolyzable tannins and their gut microbial metabolites on SARS-CoV-2 main protease. J Agric Food Chem. 2021;69(41):12197–12208.
  • Adelusi TI, Oyedele A-QK, Monday OE, Boyenle ID, Idris MO, Ogunlana AT, Ayoola AM, Fatoki JO, Kolawole OE, David KB, et al. Dietary polyphenols mitigate SARS-CoV-2 main protease (Mpro)–molecular dynamics, molecular mechanics, and density functional theory investigations. J Mol Struct. 2022;1250:131879.
  • Rudrapal M, Issahaku AR, Agoni C, Bendale AR, Nagar A, Soliman MES, Lokwani D. In silico screening of phytopolyphenolics for the identification of bioactive compounds as novel protease inhibitors effective against SARS-CoV-2. J Biomol Struct Dyn. 2022;40(20):10437–10453.
  • Rudrapal M, Celik I, Chinnam S, Azam Ansari M, Khan J, Alghamdi S, Almehmadi M, Zothantluanga JH, Khairnar SJ. Phytocompounds as potential inhibitors of SARS-CoV-2 Mpro and PLpro through computational studies. Saudi J Biol Sci. 2022;29(5):3456–3465.
  • Landete JM. Ellagitannins, ellagic acid and their derived metabolites: a review about source, metabolism, functions and health. Food Res Int. 2011;44(5):1150–1160.
  • Evtyugin DD, Magina S, Evtuguin DV. Recent advances in the production and applications of ellagic acid and its derivatives. a review. Molecules. 2020;25(12):2745.
  • Ríos JL, Giner RM, Marín M, Recio MC. A pharmacological update of ellagic acid. Planta Med. 2018;84(15):1068–1093.
  • Howell AB, D'Souza DH. The pomegranate: effects on bacteria and viruses that influence human health. Evid Based Complement Alternat Med. 2013;2013:1–11.
  • Espín JC, Larrosa M, García-Conesa MT, Tomás-Barberán F. Biological significance of urolithins, the gut microbial ellagic acid-derived metabolites: the evidence so far. Evid Based Complement Alternat Med. 2013;2013:1–15.
  • Tomás-Barberán FA, González-Sarrías A, García-Villalba R, Núñez-Sánchez MA, Selma MV, García-Conesa MT, Espín JC. Urolithins, the rescue of “old” metabolites to understand a “new” concept: metabotypes as a nexus among phenolic metabolism, microbiota dysbiosis, and host health status. Mol Nutr Food Res. 2017;61(1):1500901.
  • D'Amico D, Andreux PA, Valdés P, Singh A, Rinsch C, Auwerx J. Impact of the natural compound urolithin A on health, disease, and aging. Trends Mol Med. 2021;27(7):687–699.
  • Bayle M, Neasta J, Dall’Asta M, Gautheron G, Virsolvy A, Quignard J-F, Youl E, Magous R, Guichou J-F, Crozier A, et al. The ellagitannin metabolite urolithin C is a glucose‐dependent regulator of insulin secretion through activation of L‐type calcium channels. Br J Pharmacol. 2019;176(20):4065–4078.
  • Giorgio C, Mena P, Del Rio D, Brighenti F, Barocelli E, Hassan-Mohamed I, Callegari D, Lodola A, Tognolini M. The ellagitannin colonic metabolite urolithin D selectively inhibits EphA2 phosphorylation in prostate cancer cells. Mol Nutr Food Res. 2015;59(11):2155–2167.
  • González-Barrio R, Borges G, Mullen W, Crozier A. Bioavailability of anthocyanins and ellagitannins following consumption of raspberries by healthy humans and subjects with an ileostomy. J Agric Food Chem. 2010;58(7):3933–3939.
  • Cerdá B, Espín JC, Parra S, Martínez P, Tomás-Barberán FA. The potent in vitro antioxidant ellagitannins from pomegranate juice are metabolised into bioavailable but poor antioxidant hydroxy-6H-dibenzopyran-6-one derivatives by the colonic microflora of healthy humans. Eur J Nutr. 2004;43(4):205–220.
  • Wildman SA, Crippen GM. Prediction of physicochemical parameters by atomic contributions. J Chem Inf Comput Sci. 1999;39(5):868–873.
  • Ertl P, Rohde B, Selzer P. Fast calculation of molecular polar surface area as a sum of fragment-based contributions and its application to the prediction of drug transport properties. J Med Chem. 2000;43(20):3714–3717.
  • Dardonville C. Automated techniques in pKa determination: low, medium and high-throughput screening methods. Drug Discov Today Technol. 2018;27:49–58.
  • Daina A, Zoete V. A boiled-egg to predict gastrointestinal absorption and brain penetration of small molecules. ChemMedChem. 2016;11(11):1117–1121.
  • Daina A, Michielin O, Zoete V. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep. 2017;7(1):42717.
  • Jerabek-Willemsen M, André T, Wanner R, Roth HM, Duhr S, Baaske P, Breitsprecher D. Microscale thermophoresis: interaction analysis and beyond. J Mol Struct. 2014;1077:101–113.
  • Schultes S, De Graaf C, Haaksma EEJ, De Esch IJP, Leurs R, Krämer O. Ligand efficiency as a guide in fragment hit selection and optimization. Drug Discov Today Technol. 2010;7(3):e157–e162.
  • Abad-Zapatero C, Metz JT. Ligand efficiency indices as guideposts for drug discovery. Drug Discov Today. 2005;10(7):464–469.
  • Baell JB, Holloway GA. New substructure filters for removal of pan assay interference compounds (PAINS) from screening libraries and for their exclusion in bioassays. J Med Chem. 2010;53(7):2719–2740.
  • Baell JB. Feeling nature’s PAINS: natural products, natural product drugs, and pan assay interference compounds (PAINS). J Nat Prod. 2016;79(3):616–628.
  • Zhao Y, Fang C, Zhang Q, Zhang R, Zhao X, Duan Y, Wang H, Zhu Y, Feng L, Zhao J, et al. Crystal structure of SARS-CoV-2 main protease in complex with protease inhibitor PF-07321332. Protein Cell. 2022;13(9):689–693.
  • Kneller DW, Li H, Phillips G, Weiss KL, Zhang Q, Arnould MA, Jonsson CB, Surendranathan S, Parvathareddy J, Blakeley MP, et al. Covalent narlaprevir- and boceprevir-derived hybrid inhibitors of SARS-CoV-2 main protease. Nat Commun. 2022;13(1):2268.
  • Yang KS, Leeuwon SZ, Xu S, Liu WR. Evolutionary and structural insights about potential SARS-CoV-2 evasion of nirmatrelvir. J Med Chem. 2022;65(13):8686–8698.
  • Su H, Yao S, Zhao W, Zhang Y, Liu J, Shao Q, Wang Q, Li M, Xie H, Shang W, et al. Identification of pyrogallol as a warhead in design of covalent inhibitors for the SARS-CoV-2 3CL protease. Nat Commun. 2021;12(1):3623.
  • Yang J, Cohen Stuart MA, Kamperman M. Jack of all trades: versatile catechol crosslinking mechanisms. Chem Soc Rev. 2014;43(24):8271–8298.
  • Doona CJ, Kustin K. Kinetics and mechanism of pyrogallol autoxidation: Calibration of the dynamic response of an oxygen electrode. Int J Chem Kinet. 1993;25(4):239–247.
  • Cheng T, Li X, Li Y, Liu Z, Wang R. Comparative assessment of scoring functions on a diverse test set. J Chem Inf Model. 2009;49(4):1079–1093.
  • Sándor M, Kiss R, Keseru GM. Virtual fragment docking by glide: a validation study on 190 protein − fragment complexes. J Chem Inf Model. 2010;50(6):1165–1172.
  • Mammoli A, Bianconi E, Ruta L, Riccio A, Bigiotti C, Souma M, Carotti A, Rossini S, Suvieri C, Pallotta MT, et al. Critical Assessment of a structure-based screening campaign for IDO1 inhibitors: tips and pitfalls. Int J Mol Sci. 2022;23(7):3981.
  • de Araujo IG, Pattaro-Júnior JR, Barbosa CG, Philippsen GS, Silva AR, Ioshino RS, Moraes CB, Freitas-Junior LH, Barros L, Peralta RM, et al. Potential of plant extracts in targeting SARS-CoV-2 main protease: an in vitro and in silico study. J Biomol Struct Dyn. 2023:1–10.
  • Pattaro-Júnior JR, Araújo IG, Moraes CB, Barbosa CG, Philippsen GS, Freitas-Junior LH, Guidi AC, de Mello JCP, Peralta RM, Fernandez MA, et al. Antiviral activity of Cenostigma pluviosum var. peltophoroides extract and fractions against SARS-CoV-2. J Biomol Struct Dyn. 2023;41(15):7297–7308.
  • Völgyi G, Ruiz R, Box K, Comer J, Bosch E, Takács-Novák K. Potentiometric and spectrophotometric pKa determination of water-insoluble compounds: validation study in a new cosolvent system. Anal Chim Acta. 2007;583(2):418–428.
  • Garidel P, Hegyi M, Bassarab S, Weichel M. A rapid, sensitive and economical assessment of monoclonal antibody conformational stability by intrinsic tryptophan fluorescence spectroscopy. Biotechnol J. 2008;3(9–10):1201–1211.
  • Duhr S, Braun D. Why molecules move along a temperature gradient. Proc Natl Acad Sci USA. 2006;103(52):19678–19682.
  • Abad-Zapatero C. Ligand efficiency indices for effective drug discovery. Expert Opin Drug Discov. 2007;2(4):469–488.
  • Kim S, Chen J, Cheng T, Gindulyte A, He J, He S, Li Q, Shoemaker BA, Thiessen PA, Yu B, et al. PubChem in 2021: new data content and improved web interfaces. Nucleic Acids Res. 2021;49(D1):D1388–D1395.
  • Friesner RA, Banks JL, Murphy RB, Halgren TA, Klicic JJ, Mainz DT, Repasky MP, Knoll EH, Shelley M, Perry JK, et al. Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J Med Chem. 2004;47(7):1739–1749.
  • Gidari A, Sabbatini S, Bastianelli S, Pierucci S, Busti C, Bartolini D, Stabile AM, Monari C, Galli F, Rende M, et al. SARS-CoV-2 survival on surfaces and the effect of UV-C light. Viruses. 2021;13(3):408.
  • Reed LJ, Muench H. A simple method of estimating fifty per cent endpoints. Am J Epidemiol. 1938;27(3):493–497.
  • Gidari A, Sabbatini S, Bastianelli S, Pierucci S, Busti C, Monari C, Luciani Pasqua B, Dragoni F, Schiaroli E, Zazzi M, et al. Cross-neutralization of SARS-CoV-2 B.1.1.7 and P.1 variants in vaccinated, convalescent and P.1 infected. J Infect. 2021;83(4):467–472.
  • Lai A, Bergna A, Caucci S, Clementi N, Vicenti I, Dragoni F, Cattelan AM, Menzo S, Pan A, Callegaro A, et al. Molecular tracing of SARS-CoV-2 in Italy in the first three months of the epidemic. Viruses. 2020;12(8):798.
  • Abdelnabi R, Foo CS, Jochmans D, Vangeel L, De Jonghe S, Augustijns P, Mols R, Weynand B, Wattanakul T, Hoglund RM, et al. The oral protease inhibitor (PF-07321332) protects Syrian hamsters against infection with SARS-CoV-2 variants of concern. Nat Commun. 2022;13(1):719.
  • Gidari A, Sabbatini S, Pallotto C, Bastianelli S, Pierucci S, Busti C, Schiaroli E, Francisci D. Nelfinavir: an old ally in the COVID-19 fight? Microorganisms. 2022;10(12):2471.