Synthetic Antimicrobial Peptides. V. Histidine-containing Antifungal Peptides with a “Linear” Type of Amphipathicity

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Abstract

A number of histidine-containing synthetic antifungal peptides with a “linear” type of amphipathicity (SAMP LTA) (F2Hx, H10F2, H10, where x = 7, 10, 13 and 16) have been synthesized and studied. Biological screening of such histidine-containing peptides for their antifungal and hemolytic activity was carried out. It has been shown that the presented histidine-containing SAMP LTAs are capable of effectively inhibiting the growth of opportunistic fungi Candida albicans and have low hemolytic activity in most cases not exceeding 10% even at their relatively high concentration of 400 μM in a medium containing erythrocytes. The antifungal activity of the studied peptides increases with increasing histidine residues in their composition, reaching the maximum value for the histidine-containing peptide F2H16 (MIC50 = 1.0 µM). It has been shown that as the chain length of peptides increases, their hemolytic toxicity also increases. In terms of therapeutic significance, the optimal peptides in the presented series of peptides were F2H10 and F2H13, which have higher selectivity than the short or longer peptides F2H7 or F2H16. The therapeutic index (TI) for these peptides was 233, 247, 79 and 60, respectively. It has been shown that histidine-containing derivatives of peptides with phenylalanine residues at the N-terminus of the peptide (F2H10) are less effective compared to similar peptides (H10F2) containing phenylalanine residues at the C-terminus. Among all the studied peptides, the most active was the H10 peptide (MIC50 = 0.7 µM), which does not contain phenylalanine residues, which in its antifungal activity is not only more effective than all other histidine-containing peptides, including the F2H16 peptide with 16 histidine residues, but also 4-5 times more effective than the antifungal peptide P113 (MIC50 = 3.4 µM), a short active fragment of natural histatin 5, well known in the literature. Due to its relatively low hemolytic and high antifungal activity, the presented histidine-containing SAMP LTAs have relatively high TI values, more than 60. Among all the studied peptides, peptides H10 and P113 have minimal, almost zero, hemolytic activity. However, due to its higher antifungal activity, the selectivity of peptide H10 (TI > 1400) exceeds that of peptide P113 (TI > 340) by more than 4 times. Thus, peptide H10, due to its high antifungal activity, low hemolytic toxicity and, accordingly, high therapeutic significance, can be used as a promising antifungal peptide drug.

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About the authors

N. V. Amirkhanov

Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of RAS

Author for correspondence.
Email: nariman@niboch.nsc.ru
Russian Federation, prosp. Akad. Lavrentieva 8, Novosibirsk, 630090

A. V. Bardasheva

Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of RAS

Email: nariman@niboch.nsc.ru
Russian Federation, prosp. Akad. Lavrentieva 8, Novosibirsk, 630090

V. N. Silnikov

Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of RAS

Email: nariman@niboch.nsc.ru
Russian Federation, prosp. Akad. Lavrentieva 8, Novosibirsk, 630090

N. V. Tikunova

Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of RAS

Email: nariman@niboch.nsc.ru
Russian Federation, prosp. Akad. Lavrentieva 8, Novosibirsk, 630090

References

  1. Wisplinghoff H., Bischoff T., Tallent S.M., Seifert H., Wenzel R.P., Edmond M.B. // Clin. Infect. Dis. 2004. V. 39. P. 309–317. https://doi.org/10.1086/421946
  2. Омельчук О.А., Тевяшова А.Н., Щекотихин А.Е. // Успхимии. 2018. Т. 87. С. 1206–1225. https://doi.org/10.1070/RCR4841
  3. Perlin D.S. // Clin. Infect. Dis. 2015. V. 61. P. S612– S617. https://doi.org/10.1093/cid/civ791
  4. Whaley S.G., Berkow E.L., Rybak J.M., Nishimoto A.T., Barker K.S., Rogers P.D. // Front. Microbiol. 2017. V. 7. P. 2173. https://doi.org/10.3389/fmicb.2016.02173
  5. Peschel A., Sahl H.G. // Nat. Rev. Microbiol. 2006. V. 4. P. 529–536. https://doi.org/10.1038/nrmicro1441
  6. Bahar A.A., Ren D. // Pharmaceuticals (Basel). 2013. V. 6. P. 1543–1575. https://doi.org/10.3390/ph6121543
  7. Chung P.Y., Khanum R.J. // Microbiol. Immunol. Infect. 2017. V. 50. P. 405–410. https://doi.org/10.1016/j.jmii.2016.12.005
  8. Kim H., Jang J.H., Kim S.C., Cho J.H. // J. Antimicrob. Chemother. 2014. V. 69. P. 121–132. https://doi.org/10.1093/jac/dkt322
  9. Balandin S.V., Ovchinnikova T.V. // Russ. J. Bioorg. Chem. 2016. V. 42. P. 229–248. https://doi.org/10.1134/S1068162016030055
  10. Mookherjee N., Hancock R.E. // Cell. Mol. Life Sci. 2007. V. 64. P. 922–933. https://doi.org/10.1007/s00018-007-6475-6
  11. Navon-Venezia S., Feder R., Gaidukov L., Carmeli Y., Mor A. // Antimicrob. Agents Chemother. 2002. V. 46. P. 689–694. https://doi.org/10.1128/AAC.46.3.689-694.2002
  12. Ajingi Ya.S., Jongruja N. // Russ. J. Bioorg. Chem. 2020. V. 46. P. 463–479. https://doi.org/10.1134/S1068162020040044
  13. Deslouches B., Hasek M.L., Craigo J.K., Steckbeck J.D., Montelaro R.C. // J. Med. Microbiol. 2016. V. 65. P. 554–565. https://doi.org/10.1099/jmm.0.000258
  14. Liu X., Cao R., Wang S., Jia J., Fei H. // J. Med. Chem. 2016. V. 59. P. 5238–5247. https://doi.org/10.1021/acs.jmedchem.5b02016
  15. Hollmann A., Martínez M., Noguera M.E., Augusto M.T., Disalvo A., Santos N.C., Semorile L., Maffía P.C. // Colloids Surf. B Biointerfaces. 2016. V. 141. P. 528–536. https://doi.org/10.1016/j.colsurfb.2016.02.003
  16. Clark S., Jowitt T.A., Harris L.K., Knight C.G., Dobson C.B. // Commun. Biol. 2021. V. 4. P. 605. https://doi.org/10.1038/s42003-021-02137-7
  17. Dinh T.T.T., Kim D.-H., Lee B.-J., Kim Y.-W. // Bull. Korean Chem. Soc. 2014. V. 35. P. 3632–3636. https://doi.org/10.5012/BKCS.2014.35.12.3632
  18. Tew G.N., Liu D., Chen B., Doerksen R.J., Kaplan J., Carroll P.J., Klein M.L., de Grado W.F. // Proc. Natl. Acad. Sci. USA. 2002. V. 99. P. 5110–5114. https://doi.org/10.1073/pnas.082046199
  19. Javadpour M.M., Juban M.M., Lo W.C., Bishop S.M., Alberty J.B., Cowell S.M., Becker C.L., McLaughlin M.L. // J. Med. Chem. 1996. V. 39. P. 3107− 3113. https://doi.org/10.1021/jm9509410
  20. Chen Y., Mant C.T., Farmer S.W., Hancock R.E., Vasil M.L., Hodges R.S. // J. Biol. Chem. 2005. V. 280. P. 12316–12329. https://doi.org/10.1074/jbc.m413406200
  21. Wiradharma N., Sng M., Khan M., Ong Z.Y., Yang Y.Y. // Macromol. Rapid Commun. 2013. V. 34. P. 74–80. https://doi.org/10.1002/marc.201200534
  22. Jiang Z., Vasil A.I., Hale J.D., Hancock R.E., Vasil M.L., Hodges R.S. // Biopolymers. 2008. V. 90. P. 369–383. https://doi.org/10.1002/bip.20911
  23. Huang Y.B., Huang J.F., Chen Y.X. // Protein Cell. 2010. V. 1. P. 143–152. https://doi.org/10.1007/s13238-010-0004-3
  24. Schiffer M., Edmundson A.B. // Biophys. J. 1967. V. 7. P. 121–135. https://doi.org/10.1016/S0006-3495(67)86579-2
  25. Amirkhanov N.V., Bardasheva A.V., Tikunova N.V., Pyshnyi D.V. // Russ. J. Bioorg. Chem. 2021. V. 47. P. 681–690. https://doi.org/10.1134/S106816202103002X
  26. Amirkhanov N.V., Bardasheva A.V., Tikunova N.V., Pyshnyi D.V. // Russ. J. Bioorg. Chem. 2022. V. 48. P. 937–948. https://doi.org/10.1134/S1068162022050041
  27. Rothstein D.M., Spacciapoli P., Tran L.T., Xu T., Roberts F.D., Serra M.D., Buxton D.K., Oppenheim F.G., Friden P. // Antimicrob. Agents Chemother. 2001. V. 45. P. 1367–1373. https://doi.org/10.1128/AAC.45.5.1367-1373.2001
  28. Cheng K.T., Wu C.L., Yip B.S., Chih Y.H., Peng K.L., Hsu S.Y., Yu H.Y., Cheng J.W. // Int. J. Mol. Sci. 2020. V. 21. P. 2654. https://doi.org/10.3390/ijms21072654
  29. Zolin G.V.S., Fonseca F.H.D., Zambom C.R., Garrido S.S. // Biomolecules. 2021. V. 11. P. 1209. https://doi.org/10.3390/biom11081209
  30. Helmerhorst E.J., Hof W.V., Breeuwer P., Troxler R.F., Amerongen A.V.N., Oppenheim F.G. // J. Biol. Chem. 2001. V. 276. P. 5643–5649. https://doi.org/10.1074/jbc.M008229200
  31. Oppenheim F.G., Xu T., McMillian F.M., Levitz S.M., Diamond R.D., Offner G.D., Troxler R.F. // J. Biol. Chem. 1988. V. 263. P. 7472–7477. https://pubmed.ncbi.nlm.nih.gov/3286634/
  32. Rautenbach M., Troskie A.M., Vosloo J.A. // Biochimie. 2016. V. 130. P. 132–145. https://doi.org/10.1016/j.biochi.2016.05.013
  33. Chan W.C., White P.D. // Fmoc Solid Phase Peptide Sythesis: a Practical Approach / Eds. Chan W.C., White P.D. Oxford: IRL Press, 2000. P. 64–66.
  34. Amirkhanov N.V., Tikunova N.V., Pyshnyi D.V. // Russ. J. Bioorg. Chem. 2019. V. 45. P. 833–841. https://doi.org/10.1134/S1068162019060037
  35. Konakbayeva D., Karlsson A.J. // Curr. Opin. Biotechnol. 2023. V. 81. P. 102926. https://doi.org/10.1016/j.copbio.2023.102926
  36. Puri S., Edgerton M. // Eukaryot. Cell. 2014. V. 13. P. 958–964. https://doi.org/10.1128/ec.00095-14
  37. Jang W.S., Li X.S., Sun J.N., Edgerton M. // Antimicrob. Agents Chemother. 2008. V. 52. P. 497–504. https://doi.org/10.1128/aac.01199-07
  38. Cheng Q., Zeng P. // Curr. Pharm. Des. 2022. V. 28. P. 3527–3537. https://doi.org/10.2174/1381612828666220902124856
  39. Wieprecht T., Dathe M., Epand R.M., Beyermann M., Krause E., Maloy W.L., MacDonald D.L., Bienert M. // Biochemistry. 1997. V. 36. P. 12869–12880. https://doi.org/10.1021/bi971398n
  40. Dathe M., Wieprecht T., Nikolenko H., Handel L., Maloy W.L., MacDonald D.L., Beyermann M., Bienert M. // FEBS Lett. 1997. V. 403. P. 208–212. https://doi.org/10.1016/s0014-5793(97)00055-0
  41. Okorochenkov S.A., Zheltukhina G.A., Nebol’sin V.E. // Biochem. Moscow Suppl. Ser. B. 2011. V. 5. P. 95–102. https://doi.org/10.1134/S1990750811020120
  42. Panteleev P.V., Bolosov I.A., Balandin S.V., Ovchinnikova T.V. // J. Pept. Sci. 2015. V. 21. P. 105–113. https://doi.org/10.1002/psc.2732
  43. Amirkhanov N.V., Tikunova N.V., Pyshnyi D.V. // Russ. J. Bioorg. Chem. 2018. V. 44. P. 492–503. https://doi.org/10.1134/S1068162018050035
  44. Jacobsen F., Mohammadi-Tabrisi A., Hirsch T., Mittler D., Mygind P.H., Sonksen C.P., Raventos D., Kristensen H.H., Gatermann S., Lehnhardt M., Daigeler A., Steinau H.U., Steinstraesser L. // J. Antimicrob. Chemother. 2007. V. 59. P. 493–498. https://doi.org/10.1093/jac/dkl513

Supplementary files

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2. Fig. 1. Hypothetical representation of the classical “circular” (a) and “linear” (b) types of amphipathicity of α-helical peptides. Rectangles denote hydrophilic or cationic amino acid residues, triangles denote hydrophobic residues. In the case of the classical “circular” type of amphipathicity (CCA) [6, 22, 23], the hydrophobic and hydrophilic polar surfaces of the α-helical peptide molecule are separated by a longitudinal axial line (a). In the figure, the upper surface is hydrophilic, the lower is hydrophobic (back-and-belly amphipathicity). In the case of the linear type of amphipathicity (LCA), the hydrophobic and hydrophilic (cationic) amino acid residues are located at opposite ends along the linear axis of the peptide. The hydrophobic and hydrophilic polar regions in this case are separated by a transverse line perpendicular to the longitudinal axis of the peptide (b), where one (left) end of the molecule has a hydrophilic “tail”, and the opposite (right) end has a hydrophobic “head”. On the right are two-dimensional projections of the “spiral wheels” of Schiffer and Edmundson [20, 24] of the same peptides. It is evident that the polar homogeneity of the hydrophobic and hydrophilic groups in the case of the “linear” type of amphipathicity (b) in the projection shown on the left is much higher than when the same molecule is presented in the classical form in the form of two-dimensional projections of “spiral wheels” (on the right).

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3. Fig. 2. Histogram of the reciprocal MIC₅₀ values ​​(1/MIC₅₀) of peptides in relation to fungal cultures of C. albicans cells after 24 h of incubation with peptides.

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