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Novel Blood-Brain Barrier Shuttle Peptides Discovered through the Phage Display Method.

ABSTRACT: Delivery of therapeutic agents into the brain is a major challenge in central nervous system drug development. The blood-brain barrier (BBB) prevents access of biotherapeutics to their targets in the central nervous system and, therefore, prohibits the effective treatment of many neurological disorders. To find blood-brain barrier shuttle peptides that could target therapeutics to the brain, we applied a phage display technology on a primary endothelial rat cellular model. Two identified peptides from a 12 mer phage library, GLHTSATNLYLH and VAARTGEIYVPW, were selected and their permeability was validated using the in vitro BBB model. The permeability of peptides through the BBB was measured by ultra-performance liquid chromatography-tandem mass spectrometry coupled to a triple-quadrupole mass spectrometer (UHPLC-MS/MS). We showed higher permeability for both peptides compared to N-C reversed-sequence peptides through in vitro BBB: for peptide GLHTSATNLYLH 3.3 × 10-7 cm/s and for peptide VAARTGEIYVPW 1.5 × 10-6 cm/s. The results indicate that the peptides identified by the in vitro phage display technology could serve as transporters for the administration of biopharmaceuticals into the brain. Our results also demonstrated the importance of proper BBB model for the discovery of shuttle peptides through phage display libraries.

SUBMITTER: Majerova P

PROVIDER: S-EPMC7070575 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Novel Blood-Brain Barrier Shuttle Peptides Discovered through the Phage Display Method.

Majerova Petra P Hanes Jozef J Olesova Dominika D Sinsky Jakub J Pilipcinec Emil E Kovac Andrej A

Molecules (Basel, Switzerland) 20200217 4

Delivery of therapeutic agents into the brain is a major challenge in central nervous system drug development. The blood-brain barrier (BBB) prevents access of biotherapeutics to their targets in the central nervous system and, therefore, prohibits the effective treatment of many neurological disorders. To find blood-brain barrier shuttle peptides that could target therapeutics to the brain, we applied a phage display technology on a primary endothelial rat cellular model. Two identified peptide ...[more]

PMID: 32079185

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Project description:Design of biomaterials for cell-based therapies requires presentation of specific physical and chemical cues to cells, analogous to cues provided by native extracellular matrices (ECM). We previously identified a peptide sequence with high affinity towards apatite (VTKHLNQISQSY, VTK) using phage display. The aims of this study were to identify a human MSC-specific peptide sequence through phage display, combine it with the apatite-specific sequence, and verify the specificity of the combined dual-functioning peptide to both apatite and human bone marrow stromal cells. In this study, a combinatorial phage display identified the cell binding sequence (DPIYALSWSGMA, DPI) which was combined with the mineral binding sequence to generate the dual peptide DPI-VTK. DPI-VTK demonstrated significantly greater binding affinity (1/KD) to apatite surfaces compared to VTK, phosphorylated VTK (VTKphos), DPI-VTKphos, RGD-VTK, and peptide-free apatite surfaces (p < 0.01), while significantly increasing hBMSC adhesion strength (τ50, p < 0.01). MSCs demonstrated significantly greater adhesion strength to DPI-VTK compared to other cell types, while attachment of MC3T3 pre-osteoblasts and murine fibroblasts was limited (p < 0.01). MSCs on DPI-VTK coated surfaces also demonstrated increased spreading compared to pre-osteoblasts and fibroblasts. MSCs cultured on DPI-VTK coated apatite films exhibited significantly greater proliferation compared to controls (p < 0.001). Moreover, early and late stage osteogenic differentiation markers were elevated on DPI-VTK coated apatite films compared to controls. Taken together, phage display can identify non-obvious cell and material specific peptides to increase human MSC adhesion strength to specific biomaterial surfaces and subsequently increase cell proliferation and differentiation. These new peptides expand biomaterial design methodology for cell-based regeneration of bone defects. This strategy of combining cell and material binding phage display derived peptides is broadly applicable to a variety of systems requiring targeted adhesion of specific cell populations, and may be generalized to the engineering of any adhesion surface.

Dataset Information

Novel Blood-Brain Barrier Shuttle Peptides Discovered through the Phage Display Method.

Publications

Novel Blood-Brain Barrier Shuttle Peptides Discovered through the Phage Display Method.

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