Chlorogenic Compounds from Coffee Beans Exert Activity against Respiratory Viruses

Abstract

Chlorogenic acids are secondary metabolites in diverse plants. Some chlorogenic acids extracted from traditional medicinal plants are known for their healing properties, e.g., against viral infections. Also, green coffee beans are a rich source of chlorogenic acids, with 5-O-caffeoylquinic acid being the most abundant chlorogenic acid in coffee. We previously reported the synthesis of the regioisomers of lactones, bearing different substituents on the quinidic core. Here, 3,4-O-dicaffeoyl-1,5-γ-quinide and three dimethoxycinnamoyl-γ-quinides were investigated for in vitro antiviral activities against a panel of 14 human viruses. Whereas the dimethoxycinnamoyl-γ-quinides did not show any antiviral potency in cytopathogenic effect reduction assays, 3,4-O-dicaffeoyl-1,5-γ-quinide exerted mild antiviral activity against herpes simplex viruses, adenovirus, and influenza virus. Interestingly, when the compounds were evaluated against respiratory syncytial virus, a potent antiviral effect of 3,4-O-dicaffeoyl-1,5-γ-quinide was observed against both subtypes of respiratory syncytial virus, with EC₅₀ values in the submicromolar range. Time-of-addition experiments revealed that this compound acts on an intracellular post-entry replication step. Our data show that 3,4-O-dicaffeoyl-1,5-γ-quinide is a relevant candidate for lead optimization and further mechanistic studies, and warrants clinical development as a potential anti-respiratory syncytial virus drug.

Key words

chlorogenic acids - quinides - coffee - antiviral activity - influenza virus - respiratory syncytial virus

^* These authors contributed equally to this work.

• References

• 1 Clifford MN. Chlorogenic acids and other cinnamates – nature, occurrence, dietary burden, absorption and metabolism. J Sci Food Agric 2000; 80: 1033-1043
• 2 Farah A, Donangelo CM. Phenolic compounds in coffee. Braz J Plant Physiol 2006; 18: 23-36
• 3 Clifford MN, Knight S, Surucu B, Kuhnert N. Characterization by LC-MS ⁿ of four new classes of chlorogenic acids in green coffee beans: dimethoxycinnamoylquinic acids, diferuloylquinic acids, caffeoyl-dimethoxycinnamoylquinic acids, and feruloyl-dimethoxycinnamoylquinic acids. J Agric Food Chem 2006; 54: 1957-1969
• 4 Jaiswal R, Patras MA, Eravuchira PJ, Kuhnert N. Profile and characterization of the chlorogenic acids in green Robusta coffee beans by LC-MS ⁿ : identification of seven new classes of compounds. J Agric Food Chem 2010; 58: 8722-8737
• 5 Farah A, de Paulis T, Trugo LC, Martin PR. Effect of roasting on the formation of chlorogenic acid lactones in coffee. J Agric Food Chem 2005; 53: 1505-1513
• 6 Olthof MR, Hollman PC, Katan MB. Chlorogenic acid and caffeic acid are absorbed in humans. J Nutr 2001; 131: 66-71
• 7 Nardini M, Cirillo E, Natella F, Scaccini C. Absorption of phenolic acids in humans after coffee consumption. J Agric Food Chem 2002; 50: 5735-5741
• 8 Farah A, Monteiro M, Donangelo CM, Lafay S. Chlorogenic acids from green coffee extract are highly bioavailable in humans. J Nutr 2008; 138: 2309-2315
• 9 Scalbert A, Johnson IT, Saltmarsh M. Polyphenols: antioxidants and beyond. Am J Clin Nutr 2005; 81: 215S-217S
• 10 Aquilano K, Baldelli S, Rotilio G, Ciriolo MR. Role of nitric oxide synthases in Parkinsonʼs disease: a review on the antioxidant and anti-inflammatory activity of polyphenols. Neurochem Res 2008; 33: 2416-2426
• 11 de Paulis T, Schmidt DE, Bruchey AK, Kirby MT, McDonald MP, Commers P, Lovinger DM, Martin PR. Dicinnamoylquinides in roasted coffee inhibit the human adenosine transporter. Eur J Pharmacol 2002; 442: 215-223
• 12 Vita JA. Polyphenols and cardiovascular disease: effects on endothelial and platelet function. Am J Clin Nutr 2005; 81: 292S-297S
• 13 Arts IC, Hollman PC. Polyphenols and disease risk in epidemiologic studies. Am J Clin Nutr 2005; 81: 317S-325S
• 14 Chu YF, Brown PH, Lyle BJ, Chen YM, Black RM, Williams CE, Lin YC, Hsu CW, Cheng IH. Roasted coffees high in lipophilic antioxidants and chlorogenic acid lactones are more neuroprotective than green coffees. J Agric Food Chem 2009; 57: 9801-9808
• 15 Li YL, But PPH, Ooi VEC. Antiviral activity and mode of action of caffeoylquinic acids from Schefflera heptaphylla (L.) Frodin. Antiviral Res 2005; 68: 1-9
• 16 Ojwang JO, Wang YH, Wyde PR, Fischer NH, Schuehly W, Appleman JR, Hinds S, Shimasaki CD. A novel inhibitor of respiratory syncytial virus isolated from ethnobotanicals. Antiviral Res 2005; 68: 163-172
• 17 Fan L, Wang Y, Liang N, Huang XJ, Fan CL, Wu ZL, He ZD, Li YL, Ye WC. Quinic acid derivatives and coumarin glycoside from the roots and stems of Erycibe obtusifolia . Phytochem Letters 2015; 14: 185-189
• 18 Robinson jr. WE, Cordeiro M, Abdel-Malek S, Jia Q, Chow SA, Reinecke MG, Mitchell WM. Dicaffeoylquinic acid inhibitors of human immunodeficiency virus integrase: inhibition of the core catalytic domain of human immunodeficiency virus integrase. Mol Pharmacol 1996; 50: 846-855
• 19 Kwon HC, Jung CM, Shin CG, Lee JK, Choi SU, Kim SY, Lee KR. A new caffeoyl quinic acid from Aster scaber and its inhibitory activity against human immunodeficiency virus-1 (HIV-1) integrase. Chem Pharm Bull (Tokyo) 2000; 48: 1796-1798
• 20 Wang GF, Shi LP, Ren YD, Liu QF, Liu HF, Zhang RJ, Li Z, Zhu FH, He PL, Tang W, Tao PZ, Li C, Zhao WM, Zuo JP. Anti-hepatitis B virus activity of chlorogenic acid, quinic acid and caffeic acid in vivo and in vitro . Antiviral Res 2009; 83: 186-190
• 21 Sinisi V, Forzato C, Cefarin N, Navarini L, Berti F. Interaction of chlorogenic acids and quinides from coffee with human serum albumin. Food Chem 2015; 168: 332-340
• 22 Sinisi V, Boronová K, Colomban S, Navarini L, Berti F, Forzato C. Synthesis of mono-, di-, and tri-3,4-dimethoxycinnamoyl-1,5-γ-quinides. European J Org Chem 2014; 2014: 1321-1326
• 23 Naesens L, Lenaerts L, Andrei G, Snoeck R, Van Beers D, Holý A, Balzarini J, De Clercq E. Antiadenovirus activities of several classes of nucleoside and nucleotide analogues. Antimicrob Agents Chemother 2005; 49: 1010-1016
• 24 Stevaert A, Naesens L. The influenza virus polymerase complex: an update on its structure, functions, and significance for antiviral drug design. Med Res Rev 2016; 36: 1127-1173
• 25 Dias A, Bouvier D, Crépin T, McCarthy AA, Hart DJ, Baudin F, Cusack S, Ruigrok RW. The cap-snatching endonuclease of influenza virus polymerase resides in the PA subunit. Nature 2009; 458: 914-918
• 26 Yuan P, Bartlam M, Lou Z, Chen S, Zhou J, He X, Lv Z, Ge R, Li X, Deng T, Fodor E, Rao Z, Liu Y. Crystal structure of an avian influenza polymerase PA(N) reveals an endonuclease active site. Nature 2009; 458: 909-913
• 27 Bouloy M, Plotch SJ, Krug RM. Globin mRNAs are primers for the transcription of influenza viral RNA in vitro . Proc Natl Acad Sci U S A 1978; 75: 4886-4890
• 28 Tomassini JE, Selnick H, Davies ME, Armstrong ME, Baldwin J, Bourgeois M, Hastings J, Hazuda D, Lewis J, McClements W, Ponticello G, Radzilowski E, Smith G, Tebben A, Wolfe A. Inhibition of cap (m7GpppXm)-dependent endonuclease of influenza virus by 4-substituted 2,4-dioxobutanoic acid compounds. Antimicrob Agents Chemother 1994; 38: 2827-2837
• 29 Carcelli M, Rogolino D, Bacchi A, Rispoli G, Fisicaro E, Compari C, Sechi M, Stevaert A, Naesens L. Metal-chelating 2-hydroxyphenyl amide pharmacophore for inhibition of influenza virus endonuclease. Mol Pharm 2014; 11: 304-316
• 30 Chen E, Swift RV, Alderson N, Feher VA, Feng GS, Amaro RE. Computation-guided discovery of influenza endonuclease inhibitors. ACS Med Chem Lett 2014; 5: 61-64
• 31 Rogolino D, Bacchi A, De Luca L, Rispoli G, Sechi M, Stevaert A, Naesens L, Carcelli M. Investigation of the salicylaldehyde thiosemicarbazone scaffold for inhibition of influenza virus PA endonuclease. J Biol Inorg Chem 2015; 20: 1109-1121
• 32 Stevaert A, Nurra S, Pala N, Carcelli M, Rogolino D, Shepard C, Domaoal RA, Kim B, Alfonso-Prieto M, Marras SA, Sechi M, Naesens L. An integrated biological approach to guide the development of metal-chelating inhibitors of influenza virus PA endonuclease. Mol Pharmacol 2015; 87: 323-337
• 33 Falsey AR, Hennessey PA, Formica MA, Cox C, Walsh EE. Respiratory syncytial virus infection in elderly and high-risk adults. N Engl J Med 2005; 352: 1749-1759
• 34 Borchers AT, Chang C, Gershwin ME, Gershwin LJ. Respiratory syncytial virus–a comprehensive review. Clin Rev Allergy Immunol 2013; 45: 331-379
• 35 Rivera CA, Gómez RS, Díaz RA, Céspedes PF, Espinoza JA, González PA, Riedel CA, Bueno SM, Kalergis AM. Novel therapies and vaccines against the human respiratory syncytial virus. Expert Opin Investig Drugs 2015; 24: 1613-1630
• 36 Villenave R, Shields MD, Power UF. Respiratory syncytial virus interaction with human airway epithelium. Trends Microbiol 2013; 21: 238-244
• 37 Hallak LK, Spillmann D, Collins PL, Peeples ME. Glycosaminoglycan sulfation requirements for respiratory syncytial virus infection. J Virol 2000; 74: 10508-10513
• 38 Wang G, Deval J, Hong J, Dyatkina N, Prhavc M, Taylor J, Fung A, Jin Z, Stevens SK, Serebryany V, Liu J, Zhang Q, Tam Y, Chanda SM, Smith DB, Symons JA, Blatt LM, Beigelman L. Discovery of 4′-chloromethyl-2′-deoxy-3′,5′-di-O-isobutyryl-2′-fluorocytidine (ALS-8176), a first-in-class RSV polymerase inhibitor for treatment of human respiratory syncytial virus infection. J Med Chem 2015; 58: 1862-1878
• 39 Kernan MR, Amarquaye A, Chen JL, Chan J, Sesin DF, Parkinson N, Ye Z, Barrett M, Bales C, Stoddart CA, Sloan B, Blanc P, Limbach C, Mrisho S, Rozhon EJ. Antiviral phenylpropanoid glycosides from the medicinal plant Markhamia lutea . J Nat Prod 1998; 61: 564-570
• 40 Meneghesso S, Vanderlinden E, Stevaert A, McGuigan C, Balzarini J, Naesens L. Synthesis and biological evaluation of pyrimidine nucleoside monophosphate prodrugs targeted against influenza virus. Antiviral Res 2012; 94: 35-43
• 41 Stevaert A, Dallocchio R, Dessì A, Pala N, Rogolino D, Sechi M, Naesens L. Mutational analysis of the binding pockets of the diketo acid inhibitor L-742,001 in the influenza virus PA endonuclease. J Virol 2013; 87: 10524-10538
• 42 Kim M, Kim SY, Lee HW, Shin JS, Kim P, Jung YS, Jeong HS, Hyun JK, Lee CK. Inhibition of influenza virus internalization by (−)-epigallocatechin-3-gallate. Antiviral Res 2013; 100: 460-472
• 43 Vanderlinden E, Goktas F, Cesur Z, Froeyen M, Reed ML, Russell CJ, Cesur N, Naesens L. Novel inhibitors of influenza virus fusion: structure-activity relationship and interaction with the viral hemagglutinin. J Virol 2010; 84: 4277-4288
• 44 IUPAC [Commission on the Nomenclature of Organic Chemistry (CNOC) and IUPAC-IUB Commission on Biochemical Nomenclature (CBN)]. Nomenclature of cyclitols. Recommendations, 1973. Biochem J 1976; 153: 23-31