Analysis of the interaction of para-sulfonatocalix[8]arene with free amino acids and a six residue segment of β-amyloid peptide as a potential treatment for Alzheimer’s disease

  • Elise A. Schubert
  • Veysel Kayser
  • Nial J. WheateEmail author
Original Article


In this paper we examined the host–guest complex formation between para-sulfonatocalix[8]arene, and the amino acids l-alanine (A), l-arginine (R), l-isoleucine (I), l-leucine (L), l-lysine (K), l-phenylalanine (F), l-valine (V), and a six residue peptide (KLVFFA) based on the central hydrophobic cluster of the β-amyloid peptide. In the 1H NMR spectra, the addition of sCX[8] results in upfield and downfield shifts of selective proton resonances of the native seven amino acids, and the side-chain protons of the residues in the KLVFFA peptide of between + 0.3 and − 1.02 ppm. From a Job Plot, it was found that sCX[8] can form a 1:2 host–guest complex with the amino acid phenylalanine. The nature of the host–guest interactions was further examined by fluorescence spectrophotometry, whereby sCX[8] quenched the fluorescence of phenylalanine, both as the free amino acid, and as a residue within the KLVFFA peptide, at host–guest ratios of 1.37 and 0.24, respectively. It was also found that sCX[8] binds to the β-amyloid fibril staining dye, Thioflavin-T, and enhanced its fluorescence by 347%; this interaction could have implications in future fibrillation research using sCX[8]. Overall, the findings of this study provide an insight into the mechanism by which sCX[8] can reduce the aggregation of β-amyloid peptide, and supports further research into the potential use of sCX[8] in the treatment, or prevention, of Alzheimer’s disease.


Alzheimers β-Amyloid Peptide aggregation Amino acid Host–guest Para-sulfonatocalix[8]arene 



  1. 1.
    Prince, M., Comas-Herrara, A., Knapp, M., Guerchet, M., Karagiannidou, M.: World Alzheimer Report: Improving Healthcare for People Living with Dementia. Alzheimer’s Disease International, London (2016)Google Scholar
  2. 2.
    Sanabria-Castro, A., Alvarado-Echeverría, I., Monge-Bonilla, C.: Molecular pathogenesis of Alzheimer’s disease: an update. Ann. Neurosci. 24(1), 46–54 (2017)CrossRefGoogle Scholar
  3. 3.
    Scheltens, P., Blennow, K., Breteler, M.M.B., de Strooper, B., Frisoni, G.B., Salloway, S., Van der Flier, W.M.: Alzheimer’s disease. Lancet 388(10043), 505–517 (2016)CrossRefGoogle Scholar
  4. 4.
    Chiti, F., Dobson, C.M.: Protein misfolding, amyloid formation, and human disease: A summary of progress over the last decade. Annu. Rev. Biochem. 86(1), 27–68 (2017)CrossRefGoogle Scholar
  5. 5.
    Novo, M., Freire, S., Al-Soufi, W.: Critical aggregation concentration for the formation of early amyloid-β (1–42) oligomers. Sci. Rep. 8(1), Article No.: 1783 (2018)Google Scholar
  6. 6.
    Castello, F., Paredes, J.M., Ruedas-Rama, M.J., Martin, M., Roldan, M., Casares, S., Orte, A.: Two-step amyloid aggregation: Sequential lag phase intermediates. Sci. Rep. 7, 40065 (2017)CrossRefGoogle Scholar
  7. 7.
    Klein, W.: Synaptic targeting by aβ oligomers (ADDLs) as a basis for memory loss in early Alzheimer’s disease. Alzheimer’s Dement. 2(1), Article No.: 4355 (2006)Google Scholar
  8. 8.
    Cline, E.N., Bicca, M.A., Viola, K.L., Klein, W.L.: The amyloid-β oligomer hypothesis: Beginning of the third decade. J. Alzheimer’s Dis. 64(S1), S567–S610 (2018)CrossRefGoogle Scholar
  9. 9.
    de Groot, N.S., Aviles, F.X., Vendrell, J., Ventura, S.: Mutagenesis of the central hydrophobic cluster in aβ42 Alzheimer’s peptide. FEBS J. 273(3), 658–668 (2006)CrossRefGoogle Scholar
  10. 10.
    Cukalevski, R., Boland, B., Frohm, B., Thulin, E., Walsh, D., Linse, S.: Role of aromatic side chains in amyloid β-protein aggregation. ACS Chem. Neurosci. 3(12), 1008–1016 (2012)CrossRefGoogle Scholar
  11. 11.
    Sinha, S., Lopes, D.H.J., Bitan, G.: A key role for lysine residues in amyloid β-protein folding, assembly, and toxicity. ACS Chem. Neurosci. 3(6), 473–481 (2012)CrossRefGoogle Scholar
  12. 12.
    Chromy, B.A., Nowak, R.J., Lambert, M.P., Viola, K.L., Chang, L., Velasco, P.T., Jones, B.W., Fernandez, S.J., Lacor, P.N., Horowitz, P., Finch, C.E., Krafft, G.A., Klein, W.L.: Self-assembly of aβ1–42 into globular neurotoxins. Biochemistry 42(44), 12749–12760 (2003)CrossRefGoogle Scholar
  13. 13.
    De Felice, F.G., Vieira, M.N.N., Saraiva, L.M., Figueroa-Villar, J.D., Garcia-Abreu, J., Liu, R.O.Y., Chang, L.E.I., Klein, W.L., Ferreira, S.T.: Targeting the neurotoxic species in Alzheimer’s disease: inhibitors of aβ oligomerization. FASEB J. 18(12), 1366–1372 (2004)CrossRefGoogle Scholar
  14. 14.
    Wang, Z., Chang, L., Klein, W.L., Thatcher, G.R.J., Venton, D.L.: Per-6-substituted-per-6-deoxy β-cyclodextrins inhibit the formation of β-amyloid peptide derived soluble oligomers. J. Med. Chem. 47(13), 3329–3333 (2004)CrossRefGoogle Scholar
  15. 15.
    Ogoshi, T., Yamagishi, T.: Historical background of macrocyclic compounds. Pillar[n]arenes. Monographs in supramolecular chemistry, vol. 1, pp. 1–22. The Royal Society of Chemistry, Cambridge (2015)Google Scholar
  16. 16.
    Perret, F., Lazar, A.N., Coleman, A.W.: Biochemistry of the para-sulfonatocalix[n]arenes. Chem. Commun. 23, 2425–2438 (2006)CrossRefGoogle Scholar
  17. 17.
    Moussa, Y.E., Elysia Ong, Y.Q., Perry, J.D., Cheng, Z., Kayser, V., Cruz, E., Kim, R.R., Sciortino, N., Wheate, N.J.: Demonstration of in vitro host-guest complex formation and safety of para-sulfonatocalix[8]arene as a delivery vehicle for two antibiotic drugs. J. Pharm. Sci. 107, 3105–3111 (2018)CrossRefGoogle Scholar
  18. 18.
    Wang, Z., Tao, S., Dong, X., Sun, Y.: para-Sulfonatocalix[n]arenes inhibit amyloid β-peptide fibrillation and reduce amyloid cytotoxicity. Chem. Asian. J. 12(3), 341–346 (2017)CrossRefGoogle Scholar
  19. 19.
    Kleckner, I.R., Foster, M.P.: An introduction to NMR-based approaches for measuring protein dynamics. Biochim. Biophys. Acta 1814(8), 942–968 (2011)CrossRefGoogle Scholar
  20. 20.
    Gokel, G.W., Atwood, J.L.: General principles of supramolecular chemistry and molecular recognition. In: Atwood, J. (ed.) Comprehensive Supramolecular Chemistry II, vol. 1, p. 440. Oliver Walter, London (2017)Google Scholar
  21. 21.
    Birks, J.: Photophysics of Aromatic Molecules. Wiley, London (1970)Google Scholar
  22. 22.
    Avram, L., Iron, M.A., Bar-Shir, A.: Amplifying undetectable NMR signals to study host-guest interactions and exchange. Chem. Sci. 7(12), 6905–6909 (2016)CrossRefGoogle Scholar
  23. 23.
    Nilsson, M.R.: Techniques to study amyloid fibril formation in vitro. Methods 34(1), 151–160 (2004)CrossRefGoogle Scholar
  24. 24.
    Saravanan, C., Ashwin, B.M., Senthilkumaran, M., Muthu Mareeswaran, P.: Supramolecular complexation of biologically important thioflavin-T with p-sulfonatocalix[4]arene. ChemistrySelect 3(9), 2528–2535 (2018)CrossRefGoogle Scholar
  25. 25.
    Amdursky, N., Erez, Y., Huppert, D.: Molecular rotors: what lies behind the high sensitivity of the thioflavin-T fluorescent marker. Acc. Chem. Res. 45(9), 1548–1557 (2012)CrossRefGoogle Scholar

Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  1. 1.Sydney Pharmacy School, Faculty of Medicine and HealthThe University of SydneySydneyAustralia
  2. 2.Sydney HospitalSydneyAustralia

Personalised recommendations