Beta-endorphin chimeric peptides: Transport through the blood-brain barrier in vivo and cleavage of disulfide linkage by brain

Journal Article · Thu Feb 01 04:00:00 EST 1990 · Endocrinology; (USA)

DOI:https://doi.org/10.1210/endo-126-2-977· OSTI ID:6945763

Pardridge, W M; Triguero, D; Buciak, J L ^[1]

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1. UCLA School of Medicine (USA)

Water soluble peptides are normally not transported through the blood-brain barrier (BBB). Chimeric peptides may be transportable through the BBB and are formed by the covalent coupling of a nontransportable peptide to a transportable peptide vector, e.g. cationized albumin, using disulfide-based coupling reagents such as N-succinimidyl 3-(2-pyridyldithio(propionate)) (SPDP). The transcytosis of peptide into brain parenchyma, as opposed to vascular sequestration of blood-borne peptide, was quantified using an internal carotid artery perfusion/capillary depletion method. It is shown that (125I)beta-endorphin is not transported through the BBB, but is rapidly cleaved to free (125I) tyrosine via capillary peptidase. Therefore, chimeric peptide was prepared using (125I) (D-Ala2)beta-endorphin (DABE), owing to the resistance of this analogue to peptidase degradation. The (125I) DABE-cationized albumin chimeric peptide is shown to enter brain parenchyma at a rate comparable to that reported previously for unconjugated cationized albumin. When the (125I) DABE-cationized albumin chimeric peptide was incubated with rat brain homogenate at 37 C, the free (125I) DABE was liberated from the cationized albumin conjugate prior to its subsequent degradation into free (125I) tyrosine. Approximately 50% of the chimeric peptide was cleaved within 60 sec of incubation at 37 C. These studies demonstrate that (1) (125I)beta-endorphin is not transported through the BBB in its unconjugated form, (2) a (125I) DABE-cationized albumin chimeric peptide is transported through the BBB into brain parenchyma at a rate comparable to the unconjugated cationized albumin, and (3) brain contains the necessary disulfide reductases for rapid cleavage of the chimeric peptide into free beta-endorphin and this cleavage occurs before degradation of the (125I) DABE into (125I) tyrosine.

• OSTI ID: 6945763
• Journal Information: Endocrinology; (USA), Journal Name: Endocrinology; (USA) Vol. 126:2; ISSN ENDOA; ISSN 0013-7227
• Country of Publication: United States
• Language: English

Related Subjects

550201* -- Biochemistry-- Tracer Techniques
59 BASIC BIOLOGICAL SCIENCES
ALBUMINS
AMINO ACIDS
ANIMALS
AUTONOMIC NERVOUS SYSTEM AGENTS
BETA DECAY RADIOISOTOPES
BLOOD-BRAIN BARRIER
CARBOXYLIC ACIDS
CLEAVAGE
CRYSTAL STRUCTURE
DAYS LIVING RADIOISOTOPES
DISULFIDES
DRUGS
ELECTRON CAPTURE RADIOISOTOPES
ENDORPHINS
ENZYMES
HYDROLASES
HYDROXY ACIDS
INTERMEDIATE MASS NUCLEI
IODINE 125
IODINE ISOTOPES
ISOTOPE APPLICATIONS
ISOTOPES
MAMMALS
MEMBRANE TRANSPORT
MICROSTRUCTURE
NEUROREGULATORS
NUCLEI
ODD-EVEN NUCLEI
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANIC SULFUR COMPOUNDS
PEPTIDE HYDROLASES
PEPTIDES
PROTEINS
RADIOISOTOPES
RATS
REAGENTS
RODENTS
TRACER TECHNIQUES
TYROSINE
VERTEBRATES