Design, Synthesis and Biological Evaluation of Glutathione Peptidomimetics as Components of Anti-Parkinson Prodrugs

More, Swati S.; Vince, Robert

doi:10.1021/jm800239v

Cited by 58 publications

(41 citation statements)

References 22 publications

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“…This was in accordance with our observations with the properties of similar previously reported analogues and derivatives of Ψ-GSH. 21,22 Formation of the γ-glutamyl cysteine amide bond is a rate-limiting step in the synthesis of GSH, a fact that compounds the GCL deficiency in aging and Alzheimer's disease afflicted tissue. 15 Provision of a γ-glutamyl cysteine motif in such cases would address that crucial deficiency.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Potential of a γ-Glutamyl-Transpeptidase-Stable Glutathione Analogue against Amyloid-β Toxicity

Vince

2012

ACS Chem. Neurosci.

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The antioxidant properties of glutathione (GSH) and their relevance to oxidative stress induced pathological states such as Alzheimer's disease is well-established. The utility of GSH itself as a pharmacotherapeutic agent for such disorders is limited because of the former's lability to breakdown through amide cleavage by the ubiquitous enzyme γ-glutamyl transpeptidase (γ-GT). In the present study, a GSH analogue, Ψ-GSH, where the γ-glutamylcysteine amide linkage is replaced with a ureide linkage, was synthesized. Ψ-GSH was found to be stable toward γ-GT mediated breakdown. Ψ-GSH fulfilled four cardinal properties of GSH, namely, traversing across the blood brain barrier (BBB) via the GSH active uptake machinery, replacing GSH in the glyoxalase-I mediated detoxification of methylglyoxal, protecting cells against chemical oxidative insult, and finally lowering the cytotoxicity of amyloid-β peptide. These results validate Ψ-GSH as a viable metabolically stable replacement for GSH and establish it as a potential preclinical candidate for treatment of oxidative stress mediated pathology.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Potential of a γ-Glutamyl-Transpeptidase-Stable Glutathione Analogue against Amyloid-β Toxicity

Vince

2012

ACS Chem. Neurosci.

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“…38 Nevertheless, other strategies based on L-DOPA derivatives are being developed to avoid side-effects and focus the targeting at the CNS by means of increasing the delivery efficiency [40][41] or its selective conversion in there. 42 Nipecotic acid (NIP) is a GABA reuptake inhibitor with great therapeutic potential if it would be able to cross the BBB. [43][44][45] GABA is the primary inhibitory neurotransmitter in the CNS, and decreased levels of this molecule are associated with several brain disorders.…”

Section: Transport Ability Of (Phpro) 4 Shuttle Using the Pampa Assaymentioning

confidence: 99%

Lipid Bilayer Crossing—The Gate of Symmetry. Water-Soluble Phenylproline-Based Blood-Brain Barrier Shuttles

et al. 2015

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Drug delivery to the brain can be achieved by various means, including blood-brain barrier (BBB) disruption, neurosurgical-based approaches, and molecular design. Recently, passive diffusion BBB shuttles have been developed to transport low-molecular-weight drug candidates to the brain which would not be able to cross unaided. The low water solubility of these BBB shuttles has, however, prevented them from becoming a mainstream tool to deliver cargos across membranes. Here, we describe the design, synthesis, physicochemical characterization, and BBB-transport properties of phenylproline tetrapeptides, (PhPro)4, an improved class of BBB shuttles that operates via passive diffusion. These PhPro-based BBB shuttles showed 3 orders of magnitude improvement in water solubility compared to the gold-standard (N-MePhe)4, while retaining very high transport values. Transport capacity was confirmed when two therapeutically relevant cargos, nipecotic acid and l-3,4-dihydroxyphenylalanine (i.e., l-DOPA), were attached to the shuttle. Additionally, we used the unique chiral and conformationally restricted character of the (PhPro)4 shuttle to probe its chiral interactions with the lipid bilayer of the BBB. We studied the transport properties of 16 (PhPro)4 stereoisomers using the parallel artificial membrane permeability assay and looked at differences in secondary structure. Most stereoisomers displayed excellent transport values, yet this study also revealed pairs of enantiomers with high enantiomeric discrimination and different secondary structure, where one enantiomer maintained its high transport values while the other had significantly lower values, thereby confirming that stereochemistry plays a significant role in passive diffusion. This could open the door to the design of chiral and membrane-specific shuttles with potential applications in cell labeling and oncology.

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“…l-Dopa wurde über eine Amidbindung an GSH gebunden (Abbildung 5 H); die orale Verabreichung der Konjugate an Ratten führte zu einer nachhaltigen Freisetzung von l-Dopa und Dopamin im Gehirn, wodurch die Konzentration dieser beiden Verbindungen gegenüber der Verabreichung einer äquimolaren Dosis Dopamin erhçht wurde. [57] More et al [58] …”

Section: Chemisches Freisetzungssystem (Cds)unclassified

Schleuservermittelter Transport von Wirkstoffen ins Gehirn

2011

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Während des letzten Jahrzehnts wurden im Bereich der Wirkstofffreisetzung wesentliche Fortschritte erzielt. Die Behandlung von Gehirnerkrankungen bleibt aber wegen der Blut‐Hirn‐Schranke (BHS; blood–brain barrier) noch immer eine große Herausforderung. Diese Struktur schränkt den Zugang von Wirkstoffen zu ihrem Wirkort im Zentralnervensystem stark ein. Es wurden verschiedene Strategien vorgeschlagen, um den Transport von Wirkstoffen über die BHS zu verstärken. In diesem Aufsatz konzentrieren wir uns auf einen vektorvermittelten Ansatz, bei dem der Wirkstoff an ein Schleusermolekül gekuppelt wird, das die Fähigkeit hat, die BHS zu überqueren und die Substanz ins Gehirn abzugeben.

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Design, Synthesis and Biological Evaluation of Glutathione Peptidomimetics as Components of Anti-Parkinson Prodrugs

Cited by 58 publications

References 22 publications

Potential of a γ-Glutamyl-Transpeptidase-Stable Glutathione Analogue against Amyloid-β Toxicity

Potential of a γ-Glutamyl-Transpeptidase-Stable Glutathione Analogue against Amyloid-β Toxicity

Lipid Bilayer Crossing—The Gate of Symmetry. Water-Soluble Phenylproline-Based Blood-Brain Barrier Shuttles

Schleuservermittelter Transport von Wirkstoffen ins Gehirn

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