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Anti-inflammatory and Antioxidant Peptide-Conjugates: Modulation of Activity by Charged and Hydrophobic Residues

  • K. P. Rakesh
  • R. Suhas
  • D. Channe GowdaEmail author
Article

Abstract

In the present study, antioxidant and anti-inflammatory activities of a series of quinazolinone-conjugated-peptides were investigated. Substitution of second position of the peptide template ‘GXGVP’ by different amino acids of varying hydrophobicity, charge and polarity has been studied. Quinazolinone-peptides with Trp residue emerged out as the highly potential antioxidant whereas the conjugate with Asp moiety turned to be a good anti-inflammatory agent. These data indicate that more hydrophobicity favours antioxidant property and contrarily, presence of charged species in the molecule assists the reduction of inflammation. Further, conjugates having butyl group in the heterocyclic part and free C-terminus in the peptide part exhibited good inflammation reducing property. Thus, variation of hydrophobic groups, charges and polarity of certain amino acids in the peptide segment of the conjugate could be used to develop “dual war-head” potential therapeutics for treating inflammation and allied diseases.

Keywords

Peptide-conjugates Antioxidant Anti-inflammatory Charge and hydrophobicity 

Abbreviations

QZN I

3-(4-Oxo-3,4-dihydroquinazolin-2-yl)propanoic acid

QZN II

4-(4-Oxo-3,4-dihydroquinazolin-2-yl)butanoic acid

EDCI

1-(3-Dimethylaminopropyl)-3-ethyl-carbodiimide

HOBt

N-Hydroxy benzotriazole

NMM

N-Methyl morpholine

Boc

Tert-butyloxycarbonyl

TFA

Trifluoroacetic acid

Notes

Acknowledgements

We gratefully acknowledge University Grant Commission-Basic Science Research (UGC-BSR) for the award of BSR fellowship, Center with Potential for Excellence in a Particular Area (CPEPA), University of Potential Excellence (UPE) and Department of Science and Technology-Promotion of University Research and Scientific Excellence (DST-PURSE), UGC, New Delhi for the financial assistance.

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflicts to interest.

Ethical Approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Supplementary material

10989_2017_9668_MOESM1_ESM.doc (1.5 mb)
Supplementary material 1 (DOC 1521 KB)

References

  1. Bhattacharjya S (2010) De novo designed lipopolysaccharide binding peptides: structure based development of antiendotoxic and antimicrobial drugs. Curr Med Chem 17:3080–3093CrossRefGoogle Scholar
  2. Blois MS (1958) Antioxidant determinations by the use of a stable free radical. Nature 181:1199–1200CrossRefGoogle Scholar
  3. Cacciuttolo MA, Trinh L, Lumpkin JA, Rao G (1993) Hyperoxia induces DNA damage in mammalian cells. Free Radic Biol Med 14:267–276CrossRefGoogle Scholar
  4. Chen L (2011) Destabilization of artificial biomembrane induced by the penetration of tryptophan. Appl Surf Sci 257:5070–5076CrossRefGoogle Scholar
  5. Chen HM, Muramoto K, Yamauchi F, Fujimoto K, Nokihara K (1998) Antioxidative properties of histidine-containing peptides designed from peptide fragments found in the digests of a soybean protein. J Agric Food Chem 46:49–53CrossRefGoogle Scholar
  6. Chenard BL, Menniti FS, Welch WM Jr (1999) EP Patent 900568Google Scholar
  7. Chenard BL, Menniti FS, Pagnozzi MJ (2000) Quinazolin-4-one derivatives of methaqualone substituted at C-2 define a new class of noncompetitive antagonists at AMPA receptors. Bioorg Med Chem Lett 10:1203–1205CrossRefGoogle Scholar
  8. Fogliano V, Verde V, Randazzo G, Ritieni A (1999) Method for measuring antioxidant activity and its application to monitoring the antioxidant capacity of wines. J Agric Food Chem 47:1035–1040CrossRefGoogle Scholar
  9. Fournier J, Bruneau C, Dixneuf PH, Lécolier S (1991) Ruthenium-catalyzed synthesis of symmetrical N,N’-dialkylureas directly from carbon dioxide and amines. J Org Chem 56:4456–4458CrossRefGoogle Scholar
  10. Gowda DC, Gowda BKK, Rangappa KS (2001) Synthesis and kinetics of oxidation of phenylalanyl-glycine, isoleucyl-glycine, and leucyl-glycine with anodically generated manganese (III) sulfate. A mechanistic study. Synth React Inorg Met Org Chem 31:1109–1110CrossRefGoogle Scholar
  11. Lee YL, Yen MT, Mau JL (2007) Antioxidant properties of various extracts from Hypsizigus marmoreus. Food Chem 104:1–9CrossRefGoogle Scholar
  12. Lönn P, Dowdy SF (2015) Cationic PTD/CPP-mediated macromolecular delivery: charging into the cell Expert. Opi Drug Deliv 12:1627–1636CrossRefGoogle Scholar
  13. Lönn P, Apollo DK, Xian-SC, Alexander SH, Manuel K, Khirud G, Steven FD (2016) Enhancing endosomal escape for intracellular delivery of macromolecular biologic therapeutics. Sci Rep 6:32301CrossRefGoogle Scholar
  14. Mhaske SB, Argade NP (2001) Concise and efficient synthesis of bioactive natural products pegamine, deoxyvasicinone, and (–)-vasicinone. J Org Chem 66:9038–9040CrossRefGoogle Scholar
  15. Nagaoka I, Hirota S, Niyonsaba F, Hirata M, Adachi Y, Tamura H, Tanaka A, Heumann D (2002) Augmentation of the lipopolysaccharide-neutralizing activities of human cathelicidin CAP18/LL-37-derived antimicrobial peptides by replacement with hydrophobic and cationic amino acid residues. Clin Diagn Lab Immunol 9:972–982Google Scholar
  16. Nan YH, Bang J-K, Jacob B, Park I-S, Shin SY (2012) Prokaryotic selectivity and LPS-neutralizing activity of short antimicrobial peptides designed from the human antimicrobial peptide LL-37. Peptides 35:239–247CrossRefGoogle Scholar
  17. Prasad KU, Iqbal MA, Urry DW (1985) Utilization of 1-hydroxybenzotriazole in mixed anhydride coupling reactions. Int J Pept Protein Res 25:408–413CrossRefGoogle Scholar
  18. Re R, Pellegrini N, Proteggente A, Pannala A, Yang M, Rice-Evans C (1999) Antioxidant activity applying an improved ABTS radical cation decolorization assay. Free Radic Biol Med 26:1231–1237CrossRefGoogle Scholar
  19. Roberts MJ, Bentley MD, Harris JM (2002) Chemistry for peptide and protein PEGylation. Adv Drug Deliv Rev 54:459–476CrossRefGoogle Scholar
  20. Rydberg HA, Matson M, Amand HL, Esbjörner EK, Nordén B (2012) Effects of tryptophan content and backbone spacing on the uptake efficiency of cell-penetrating peptides. Biochemistry 51:5531–5539CrossRefGoogle Scholar
  21. Santagati NA, Bousquet E, Spadaro A (1999) 4-Quinazolinones: Synthesis and reduction of prostaglandin E2 production. Farmaco 54:780–784CrossRefGoogle Scholar
  22. Shinde UA, Phadke AS, Nair AM, Mungantiwar AA, Dikshit VJ, Saraf MN (1999) Membrane stabilizing activity- a possible mechanism of action for the anti-inflammatory activity of Cedrus deodara wood oil. Fitoterapia 70:251–257CrossRefGoogle Scholar
  23. Takayama K (2009) Enhanced intracellular delivery using arginine-rich peptides by the addition of penetration accelerating sequences (Pas). J Control Release 138:128–133CrossRefGoogle Scholar
  24. Takayama K (2012) Effect of the attachment of a penetration accelerating sequence and the influence of hydrophobicity on octaarginine-mediated intracellular delivery. Mol Pharm 9:1222–1230CrossRefGoogle Scholar
  25. Wei L, Yang J, He X, Mo G, Hong J, Yan X, Lin D, Lai R (2013) Structure and function of a potent lipopolysaccharide-binding antimicrobial and anti-inflammatory peptide. J Med Chem 56:3546–3556CrossRefGoogle Scholar
  26. Wohlrab A, Lamer R, VanNieuwenhze MS (2007) Total synthesis of Plusbacin A3: a depsipeptide antibiotic active against vancomycin-resistant bacteria. J Am Chem Soc 129:4175–4177CrossRefGoogle Scholar
  27. Yang X, Jin H, Liu K, Gu Q, Xu X (2011) A novel peptide derived from human pancreatitis-associated protein inhibits inflammation in vivo and in vitro and blocks NF-Kappa B signaling pathway. PLoS ONE 6:e29155CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2017

Authors and Affiliations

  1. 1.Department of Studies in ChemistryUniversity of MysoreMysuruIndia
  2. 2.Postgraduate Department of ChemistryJSS College of Arts, Commerce and ScienceMysuruIndia

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