Structure-activity Relationship of a Peptide Permeation Enhancer

Overview

Journal Tissue Barriers

Specialties Anatomy & Histology
Biology
Physiology

Date 2022 Apr 4

PMID 35369830

Authors

Joel Brunner

Gerrit Borchard

Affiliations

Soon will be listed here.

Abstract

The pentapeptide L-R5 has previously been shown to transiently increase the permeability of nasal epithelial cell layers , allowing paracellular transport of molecules of up to 4 kDa. Protein kinase C zeta (PKC ζ), a member of a family of serine/threonine kinases was shown to be involved in tight junction modulation induced by L-R5. We show here that the ability of L-R5 to modulate tight junctions is comparable to other permeability enhancers such as bilobalide, latrunculin A or C. Interaction of the peptide with the target protein occurs via electrostatic interaction, with the presence of positive charges being essential for its functionality. L-R5 is myristoylated to allow quick cell entry and onset of activity. While no epithelial cytotoxicity was detected, the hydrophobic myristoyl rest was shown to cause haemolysis. Taken together, these data show that a structural optimization of L-R5 may be possible, both from a toxicological and an efficacy point of view.

References

Twarog C, Fattah S, Heade J, Maher S, Fattal E, Brayden D . Intestinal Permeation Enhancers for Oral Delivery of Macromolecules: A Comparison between Salcaprozate Sodium (SNAC) and Sodium Caprate (C). Pharmaceutics. 2019; 11(2). PMC: 6410172. DOI: 10.3390/pharmaceutics11020078. View

Ragupathy S, Brunner J, Borchard G . Short peptide sequence enhances epithelial permeability through interaction with protein kinase C. Eur J Pharm Sci. 2021; 160:105747. DOI: 10.1016/j.ejps.2021.105747. View

Ratnayake W, Apostolatos C, Breedy S, Dennison C, Hill R, Acevedo-Duncan M . Atypical PKCs activate Vimentin to facilitate prostate cancer cell motility and invasion. Cell Adh Migr. 2021; 15(1):37-57. PMC: 7889213. DOI: 10.1080/19336918.2021.1882782. View

Guo H, Gu F, Li W, Zhang B, Niu R, Fu L . Reduction of protein kinase C zeta inhibits migration and invasion of human glioblastoma cells. J Neurochem. 2009; 109(1):203-13. DOI: 10.1111/j.1471-4159.2009.05946.x. View

Luo X, Guo L, Zhang J, Xu Y, Gu W, Feng L . Tight Junction Protein Occludin Is a Porcine Epidemic Diarrhea Virus Entry Factor. J Virol. 2017; 91(10). PMC: 5411586. DOI: 10.1128/JVI.00202-17. View

Maher S, Leonard T, Jacobsen J, Brayden D . Safety and efficacy of sodium caprate in promoting oral drug absorption: from in vitro to the clinic. Adv Drug Deliv Rev. 2009; 61(15):1427-49. DOI: 10.1016/j.addr.2009.09.006. View

Gradauer K, Dunnhaupt S, Vonach C, Szollosi H, Pali-Scholl I, Mangge H . Thiomer-coated liposomes harbor permeation enhancing and efflux pump inhibitory properties. J Control Release. 2012; 165(3):207-15. PMC: 3560037. DOI: 10.1016/j.jconrel.2012.12.001. View

Alqahtani S . In silico ADME-Tox modeling: progress and prospects. Expert Opin Drug Metab Toxicol. 2017; 13(11):1147-1158. DOI: 10.1080/17425255.2017.1389897. View

Laudanna C, Mochly-Rosen D, Liron T, Constantin G, Butcher E . Evidence of zeta protein kinase C involvement in polymorphonuclear neutrophil integrin-dependent adhesion and chemotaxis. J Biol Chem. 1998; 273(46):30306-15. DOI: 10.1074/jbc.273.46.30306. View

10.

Ragupathy S, Esmaeili F, Paschoud S, Sublet E, Citi S, Borchard G . Toll-like receptor 2 regulates the barrier function of human bronchial epithelial monolayers through atypical protein kinase C zeta, and an increase in expression of claudin-1. Tissue Barriers. 2014; 2:e29166. PMC: 4117686. DOI: 10.4161/tisb.29166. View

11.

Stuart R, Nigam S . Regulated assembly of tight junctions by protein kinase C. Proc Natl Acad Sci U S A. 1995; 92(13):6072-6. PMC: 41644. DOI: 10.1073/pnas.92.13.6072. View

12.

Song H, Zhang J, He W, Wang P, Wang F . Activation of Cofilin Increases Intestinal Permeability Depolymerization of F-Actin During Hypoxia . Front Physiol. 2019; 10:1455. PMC: 6901426. DOI: 10.3389/fphys.2019.01455. View

13.

Dempsey E, Newton A, Mochly-Rosen D, Fields A, Reyland M, Insel P . Protein kinase C isozymes and the regulation of diverse cell responses. Am J Physiol Lung Cell Mol Physiol. 2000; 279(3):L429-38. DOI: 10.1152/ajplung.2000.279.3.L429. View

14.

Fields A, Murray N . Protein kinase C isozymes as therapeutic targets for treatment of human cancers. Adv Enzyme Regul. 2008; 48:166-78. PMC: 2586109. DOI: 10.1016/j.advenzreg.2007.11.014. View

15.

Sakane F, Hoshino F, Ebina M, Sakai H, Takahashi D . The Roles of Diacylglycerol Kinase α in Cancer Cell Proliferation and Apoptosis. Cancers (Basel). 2021; 13(20). PMC: 8534027. DOI: 10.3390/cancers13205190. View

16.

Lovstad R . Fatty acid induced hemolysis. Protective action of ceruloplasmin, albumins, thiols and vitamin C. Int J Biochem. 1986; 18(9):771-5. DOI: 10.1016/0020-711x(86)90052-2. View

17.

Marchant G . Hormesis and toxic torts. Hum Exp Toxicol. 2008; 27(2):97-107. DOI: 10.1177/0960327107086567. View

18.

Cheney K, White A, Mudianta I, Winters A, Quezada M, Capon R . Choose Your Weaponry: Selective Storage of a Single Toxic Compound, Latrunculin A, by Closely Related Nudibranch Molluscs. PLoS One. 2016; 11(1):e0145134. PMC: 4720420. DOI: 10.1371/journal.pone.0145134. View

19.

Cario E, Gerken G, Podolsky D . Toll-like receptor 2 enhances ZO-1-associated intestinal epithelial barrier integrity via protein kinase C. Gastroenterology. 2004; 127(1):224-38. DOI: 10.1053/j.gastro.2004.04.015. View

20.

Ma H, OKennedy R . The Structure of Natural and Recombinant Antibodies. Methods Mol Biol. 2015; 1348:7-11. DOI: 10.1007/978-1-4939-2999-3_2. View