Improving Membrane Activity and Cargo Delivery Efficacy of a Cell-Penetrating Peptide by Loading with Carboranes

Overview

Journal Pharmaceutics

Publisher MDPI

Date 2021 Dec 28

PMID 34959356

Citations 2

Authors

Tamara Lutzenburg

Nele Burdina

Matthias S Scholz

Ines Neundorf

Affiliations

Soon will be listed here.

Abstract

Cell-penetrating peptides (CPPs) have emerged as versatile tools to increase the intracellular accumulation of different kinds of cargoes. For an efficient cellular uptake and drug delivery, their organization into a distinct and stable secondary structure at the outer surface of the plasma membrane is a hallmark and supports optimal lipid-peptide interactions. Incorporation of hydrophobic moieties, such as carboranes (CBs), has the potential to increase the lipophilicity of peptides, and thus, to facilitate the formation of secondary structures. Herein, we present synthesis and biophysical as well as biological characterization of carborane-CPP conjugates having incorporated one or more CB clusters. Our results highlight the possibility to modulate the secondary structure of CPPs by the addition of CB's leading to constructs with altered membrane activity and promising use in terms of nucleic acid delivery.

Citing Articles

Gemini surfactant-like peptide-based nanocages with β-sheet-enhanced stability and encapsulation efficiency of hydrophobic anticancer drugs.

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References

Klimpel A, Stillger K, Wiederstein J, Kruger M, Neundorf I . Cell-permeable CaaX-peptides affect K-Ras downstream signaling and promote cell death in cancer cells. FEBS J. 2020; 288(9):2911-2929. DOI: 10.1111/febs.15612. View

Birch D, Christensen M, Staerk D, Franzyk H, Nielsen H . Fluorophore labeling of a cell-penetrating peptide induces differential effects on its cellular distribution and affects cell viability. Biochim Biophys Acta Biomembr. 2017; 1859(12):2483-2494. DOI: 10.1016/j.bbamem.2017.09.015. View

Scholz M, Wingen L, Brunst S, Wittmann S, Cardoso I, Weizel L . Soluble epoxide hydrolase inhibitors with carboranes as non-natural 3-D pharmacophores. Eur J Med Chem. 2019; 185:111766. DOI: 10.1016/j.ejmech.2019.111766. View

Worm D, Hoppenz P, Els-Heindl S, Kellert M, Kuhnert R, Saretz S . Selective Neuropeptide Y Conjugates with Maximized Carborane Loading as Promising Boron Delivery Agents for Boron Neutron Capture Therapy. J Med Chem. 2019; 63(5):2358-2371. DOI: 10.1021/acs.jmedchem.9b01136. View

Hedegaard S, Derbas M, Kjellerup Lind T, Kasimova M, Christensen M, Michaelsen M . Fluorophore labeling of a cell-penetrating peptide significantly alters the mode and degree of biomembrane interaction. Sci Rep. 2018; 8(1):6327. PMC: 5910404. DOI: 10.1038/s41598-018-24154-z. View

Pisa M, Chassaing G, Swiecicki J . Translocation mechanism(s) of cell-penetrating peptides: biophysical studies using artificial membrane bilayers. Biochemistry. 2014; 54(2):194-207. DOI: 10.1021/bi501392n. View

Tang H, Yin L, Kim K, Cheng J . Helical Poly(arginine) Mimics with Superior Cell-Penetrating and Molecular Transporting Properties. Chem Sci. 2014; 4(10):3839-3844. PMC: 4232443. DOI: 10.1039/C3SC51328A. View

Negrete-Hurtado A, Overhoff M, Bera S, De Bruyckere E, Schatzmuller K, Kye M . Autophagy lipidation machinery regulates axonal microtubule dynamics but is dispensable for survival of mammalian neurons. Nat Commun. 2020; 11(1):1535. PMC: 7093409. DOI: 10.1038/s41467-020-15287-9. View

Ihsan A, Nargis M, Koyama Y . Effects of the Hydrophilic-Lipophilic Balance of Alternating Peptides on Self-Assembly and Thermo-Responsive Behaviors. Int J Mol Sci. 2019; 20(18). PMC: 6770757. DOI: 10.3390/ijms20184604. View

10.

Rego de Figueiredo I, Freire J, Flores L, Veiga A, Castanho M . Cell-penetrating peptides: A tool for effective delivery in gene-targeted therapies. IUBMB Life. 2014; 66(3):182-194. DOI: 10.1002/iub.1257. View

11.

Lakshminarayanan R, Fan D, Du C, Moradian-Oldak J . The role of secondary structure in the entropically driven amelogenin self-assembly. Biophys J. 2007; 93(10):3664-74. PMC: 2072069. DOI: 10.1529/biophysj.107.113936. View

12.

Gessner I, Neundorf I . Nanoparticles Modified with Cell-Penetrating Peptides: Conjugation Mechanisms, Physicochemical Properties, and Application in Cancer Diagnosis and Therapy. Int J Mol Sci. 2020; 21(7). PMC: 7177461. DOI: 10.3390/ijms21072536. View

13.

Yamashita H, Demizu Y, Shoda T, Sato Y, Oba M, Tanaka M . Amphipathic short helix-stabilized peptides with cell-membrane penetrating ability. Bioorg Med Chem. 2014; 22(8):2403-8. DOI: 10.1016/j.bmc.2014.03.005. View

14.

Sparks D, Lund-Katz S, Phillips M . The charge and structural stability of apolipoprotein A-I in discoidal and spherical recombinant high density lipoprotein particles. J Biol Chem. 1992; 267(36):25839-47. View

15.

Hoppenz P, Els-Heindl S, Kellert M, Kuhnert R, Saretz S, Lerchen H . A Selective Carborane-Functionalized Gastrin-Releasing Peptide Receptor Agonist as Boron Delivery Agent for Boron Neutron Capture Therapy. J Org Chem. 2019; 85(3):1446-1457. DOI: 10.1021/acs.joc.9b02406. View

16.

Karle I . Controls exerted by the Aib residue: helix formation and helix reversal. Biopolymers. 2002; 60(5):351-65. DOI: 10.1002/1097-0282(2001)60:5<351::AID-BIP10174>3.0.CO;2-U. View

17.

Lutzenburg T, Neundorf I, Scholz M . Direct carborane-peptide conjugates: Synthesis and evaluation as non-natural lipopeptide mimetics. Chem Phys Lipids. 2018; 213:62-67. DOI: 10.1016/j.chemphyslip.2018.03.009. View

18.

Klimpel A, Lutzenburg T, Neundorf I . Recent advances of anti-cancer therapies including the use of cell-penetrating peptides. Curr Opin Pharmacol. 2019; 47:8-13. DOI: 10.1016/j.coph.2019.01.003. View

19.

Copolovici D, Langel K, Eriste E, Langel U . Cell-penetrating peptides: design, synthesis, and applications. ACS Nano. 2014; 8(3):1972-94. DOI: 10.1021/nn4057269. View

20.

Neundorf I, Rennert R, Hoyer J, Schramm F, Lobner K, Kitanovic I . Fusion of a Short HA2-Derived Peptide Sequence to Cell-Penetrating Peptides Improves Cytosolic Uptake, but Enhances Cytotoxic Activity. Pharmaceuticals (Basel). 2016; 2(2):49-65. PMC: 3978507. DOI: 10.3390/ph2020049. View