New diketopiperazines as vectors for peptide protection and brain delivery: Synthesis and biological evaluation.
New strategies allowing the transfer of molecules, especially peptides, through the blood-brain barriers are a major pharmacological challenge for the treatment of brain diseases. The present study aims at evaluating in vivo the cerebral bioavailability of carrier systems, based on small and functionalizable 2,5-diketopiperazine (DKP) motifs. We studied 2 different cyclo(Lys-Lys) DKP scaffolds alone and a cyclo(Lys-Gly) DKP carrier bearing as peptide model, the tau protein hexapeptide VQIVYK sequence. The different carrier systems were synthesized and radiolabeled using one of the free domains. The stability, biodistribution, and ability to cross blood-brain barrier were investigated in vivo in mice for99mTc-DKP scaffolds,99mTc-HVQIVYK peptide alone, and99mTc-DKP-VQIVYK.125I-labelled bovine serum albumin was used as negative control for brain uptake. Both radiolabeled DKPs scaffolds and99mTc-DKP-VQIVYK showed a high stability, while peptide99mTc-HVQIVYK alone was quickly degraded in vivo. The presence of99mTc-DKPs scaffolds and99mTc-DKP-VQIVYK was observed in the ventricular and subarachnoid spaces and to a lower extent in the brain parenchyma up to 45 minutes post-injection in mice. This work highlights the potentiality of DKP scaffolds as vectors to transport peptides into the brain by limiting proteolysis and favoring cerebral bioavailability.
INSERM U1039, La Tronche, France. angevi@hotmail.fr.|Université Grenoble Alpes, Grenoble, France. angevi@hotmail.fr.
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0000-0001-5422-2934
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Virgone-Carlotta
Université Grenoble Alpes, Grenoble, France.|Département de Chimie Moléculaire, Centre National de la Recherche Scientifique, UMR 5250, Grenoble, France.
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Dufour
INSERM U1039, La Tronche, France.|Université Grenoble Alpes, Grenoble, France.
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Bacot
INSERM U1039, La Tronche, France.|Université Grenoble Alpes, Grenoble, France.
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Ahmadi
Université Grenoble Alpes, Grenoble, France.|Département de Chimie Moléculaire, Centre National de la Recherche Scientifique, UMR 5250, Grenoble, France.
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Cornou
Université Grenoble Alpes, Grenoble, France.|Département de Chimie Moléculaire, Centre National de la Recherche Scientifique, UMR 5250, Grenoble, France.
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Moni
Université Grenoble Alpes, Grenoble, France.|Département de Chimie Moléculaire, Centre National de la Recherche Scientifique, UMR 5250, Grenoble, France.
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Garcia
Université Grenoble Alpes, Grenoble, France.|Département de Chimie Moléculaire, Centre National de la Recherche Scientifique, UMR 5250, Grenoble, France.
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Chierici
INSERM U1039, La Tronche, France.|Université Grenoble Alpes, Grenoble, France.
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Garin
INSERM U1039, La Tronche, France.|Université Grenoble Alpes, Grenoble, France.
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Marti-Batlle
INSERM U1039, La Tronche, France.|Université Grenoble Alpes, Grenoble, France.
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Perret
INSERM, U1028; CNRS, UMR5292, Lyon, France.|BIP Platform, Lyon Neuroscience Research Center, Université Lyon 1, Lyon, France.
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Ghersi-Egea
INSERM U1039, La Tronche, France.|Université Grenoble Alpes, Grenoble, France.
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Moulin Sallanon
INSERM U1039, La Tronche, France.|Université Grenoble Alpes, Grenoble, France.
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Fagret
INSERM U1039, La Tronche, France.|Université Grenoble Alpes, Grenoble, France.
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Ghezzi
D000595:Amino Acid Sequence; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D060326:Chemistry Techniques, Synthetic; D054659:Diketopiperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D004337:Drug Carriers / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D004355:Drug Stability; D051379:Mice; D009842:Oligopeptides / Q000737:chemistry* / Q000378:metabolism*; D010539:Permeability; D013667:Technetium / Q000737:chemistry; D014018:Tissue Distribution
D054659:Diketopiperazines; D004337:Drug Carriers; D009842:Oligopeptides; D013667:Technetium
biodistribution; blood-brain barrier; diketopiperazines; peptides; vectors