Can Amphipathic Helices Influence the CNS Antinociceptive Activity of Glycopeptides Related to β-endorphin?

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2014 Mar 1

PMID 24576160

Citations 8

Authors

Yingxue Li

Lindsay St Louis

Brian I Knapp

Dhanasekaran Muthu

Bobbi Anglin

Denise Giuvelis

Jean M Bidlack

Edward J Bilsky

Robin Polt

Affiliations

Soon will be listed here.

Abstract

Glycosylated β-endorphin analogues of various amphipathicity were studied in vitro and in vivo in mice. Opioid binding affinities of the O-linked glycopeptides (mono- or disaccharides) and unglycosylated peptide controls were measured in human receptors expressed in CHO cells. All were pan-agonists, binding to μ-, δ-, or κ-opioid receptors in the low nanomolar range (2.2-35 nM K(i)'s). The glycoside moiety was required for intravenous (i.v.) but not for intracerebroventricular (i.c.v.) activity. Circular dichroism and NMR indicated the degree of helicity in H2O, aqueous trifluoroethanol, or micelles. Glycosylation was essential for activity after i.v. administration. It was possible to manipulate the degree of helicity by the alteration of only two amino acid residues in the helical address region of the β-endorphin analogues without destroying μ-, δ-, or κ-agonism, but the antinociceptive activity after i.v. administration could not be directly correlated to the degree of helicity in micelles.

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References

Costantini S, Colonna G, Facchiano A . Amino acid propensities for secondary structures are influenced by the protein structural class. Biochem Biophys Res Commun. 2006; 342(2):441-51. DOI: 10.1016/j.bbrc.2006.01.159. View

Habgood M, Begley D, Abbott N . Determinants of passive drug entry into the central nervous system. Cell Mol Neurobiol. 2000; 20(2):231-53. PMC: 11537553. DOI: 10.1023/a:1007001923498. View

Su J, Hodges R, Kay C . Effect of chain length on the formation and stability of synthetic alpha-helical coiled coils. Biochemistry. 1994; 33(51):15501-10. DOI: 10.1021/bi00255a032. View

Del Zoppo G . Stroke and neurovascular protection. N Engl J Med. 2006; 354(6):553-5. DOI: 10.1056/NEJMp058312. View

Piotto M, Saudek V, SKLENAR V . Gradient-tailored excitation for single-quantum NMR spectroscopy of aqueous solutions. J Biomol NMR. 1992; 2(6):661-5. DOI: 10.1007/BF02192855. View

Porreca F, Mosberg H, Hurst R, Hruby V, Burks T . Roles of mu, delta and kappa opioid receptors in spinal and supraspinal mediation of gastrointestinal transit effects and hot-plate analgesia in the mouse. J Pharmacol Exp Ther. 1984; 230(2):341-8. View

Lowery J, Raymond T, Giuvelis D, Bidlack J, Polt R, Bilsky E . In vivo characterization of MMP-2200, a mixed δ/μ opioid agonist, in mice. J Pharmacol Exp Ther. 2010; 336(3):767-78. PMC: 3061528. DOI: 10.1124/jpet.110.172866. View

Segrest J, De Loof H, Dohlman J, Brouillette C, Anantharamaiah G . Amphipathic helix motif: classes and properties. Proteins. 1990; 8(2):103-17. DOI: 10.1002/prot.340080202. View

Parkhill A, Bidlack J . Several delta-opioid receptor ligands display no subtype selectivity to the human delta-opioid receptor. Eur J Pharmacol. 2002; 451(3):257-64. DOI: 10.1016/s0014-2999(02)02241-0. View

10.

Adessi C, Soto C . Converting a peptide into a drug: strategies to improve stability and bioavailability. Curr Med Chem. 2002; 9(9):963-78. DOI: 10.2174/0929867024606731. View

11.

Varamini P, Mansfeld F, Blanchfield J, Wyse B, Smith M, Toth I . Synthesis and biological evaluation of an orally active glycosylated endomorphin-1. J Med Chem. 2012; 55(12):5859-67. DOI: 10.1021/jm300418d. View

12.

Fisher J, Harrison A, Bundy G, Wilkinson K, Rush B, Ruwart M . Peptide to glycopeptide: glycosylated oligopeptide renin inhibitors with attenuated in vivo clearance properties. J Med Chem. 1991; 34(10):3140-3. DOI: 10.1021/jm00114a026. View

13.

Polt R, Dhanasekaran M, Keyari C . Glycosylated neuropeptides: a new vista for neuropsychopharmacology?. Med Res Rev. 2005; 25(5):557-85. DOI: 10.1002/med.20039. View

14.

Begley D . The blood-brain barrier: principles for targeting peptides and drugs to the central nervous system. J Pharm Pharmacol. 1996; 48(2):136-46. DOI: 10.1111/j.2042-7158.1996.tb07112.x. View

15.

Bewley T, Li C . Evidence for tertiary structure in aqueous solutions of human beta-endorphin as shown by difference absorption spectroscopy. Biochemistry. 1983; 22(11):2671-5. DOI: 10.1021/bi00280a013. View

16.

Brasnjevic I, Steinbusch H, Schmitz C, Martinez-Martinez P . Delivery of peptide and protein drugs over the blood-brain barrier. Prog Neurobiol. 2009; 87(4):212-51. DOI: 10.1016/j.pneurobio.2008.12.002. View

17.

Hughes J, Smith T, KOSTERLITZ H, Fothergill L, Morgan B, Morris H . Identification of two related pentapeptides from the brain with potent opiate agonist activity. Nature. 1975; 258(5536):577-80. DOI: 10.1038/258577a0. View

18.

Powell M, Stewart T, Otvos Jr L, Urge L, Gaeta F, Sette A . Peptide stability in drug development. II. Effect of single amino acid substitution and glycosylation on peptide reactivity in human serum. Pharm Res. 1993; 10(9):1268-73. DOI: 10.1023/a:1018953309913. View

19.

Tsuji , Tamai I . Carrier-mediated or specialized transport of drugs across the blood-brain barrier. Adv Drug Deliv Rev. 2000; 36(2-3):277-290. DOI: 10.1016/s0169-409x(98)00084-2. View

20.

Ogawa H, Nakano M, Watanabe H, Starikov E, Rothstein S, Tanaka S . Molecular dynamics simulation study on the structural stabilities of polyglutamine peptides. Comput Biol Chem. 2008; 32(2):102-10. DOI: 10.1016/j.compbiolchem.2007.11.001. View