Glycosylated Neurotensin Analogues Exhibit Sub‐picomolar Anticonvulsant Potency in a Pharmacoresistant Model of Epilepsy

Lee, Hee Kyoung; Zhang, Liuyin; Smith, Michael L.; White, H. Steve; Bułaj, Grzegorz

doi:10.1002/cmdc.200800421

Cited by 29 publications

(28 citation statements)

References 38 publications

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“…Building blocks such as N ε -acyl-Lys and LAA can be chemically synthesized and directly coupled on resin by the Fmoc solid phase peptide synthesis (SPPS) method [18,[159][160][161]. S-Acylated cysteine is not recommended due to possible aminolysis by the α -amino group [162].…”

Section: Chemical Synthesis Methodsmentioning

confidence: 99%

Converting Peptides into Drug Leads by Lipidation

Zhang¹,

Bułaj²

2012

CMC

175

139

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Ulceration in the gastrointestinal (GI) mucosa is a common disorder in humans. It has been shown that cigarette smoking is closely related to the increase of peptic ulcer and also plays an inhibitory role on ulcer healing. However, the underlying mechanisms by which cigarette smoke exerts these adverse effects remain largely unknown. It is perhaps partly due to the complexity of chemical compositions in the smoke and furthermore their pathological actions are largely undefined. In this review, we have highlighted the potential adverse effects of the toxic chemical components in cigarette smoke and summarized their possible mechanisms of actions on ulcer formation and healing in the GI tract. We also discuss in detail how cigarette smoke disturbs cell proliferation, influences mucus synthesis and secretion, delays blood vessel formation, and interferes the innate immune responses during ulceration and repair in the GI mucosa.

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Section: Chemical Synthesis Methodsmentioning

confidence: 99%

Converting Peptides into Drug Leads by Lipidation

Zhang¹,

Bułaj²

2012

CMC

175

139

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“…The encoded protein is likely involved in the termination of the neurotensinergic signal in the central nervous system and in the gastrointestinal tract. In particular, in specific brain regions examined (amygdala, corpus callosum, and caudate nucleus), it showed strong expression, with moderate expression in cerebellum, hippocampus, substantia nigra, and thalamus [Lee et al, 2009].…”

Section: Discussionmentioning

confidence: 99%

Familial 5q12.3 Microdeletion: Evidence for a Locus Associated with Epilepsy

et al. 2017

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The clinical use of array comparative genomic hybridization (array CGH) has allowed the identification of very rare deletion and duplication disorders, such as 5q12 deletion syndrome (OMIM 615668) described as a contiguous gene deletion syndrome of chromosome 5q12. Chromosome microdeletions including band 5q12 have rarely been reported and have been associated with different phenotypes showing postnatal growth restriction, intellectual disability, epileptic seizures, hyperactivity, and ocular abnormalities. In this study, we describe a family in which array-CGH analysis revealed the presence of an interstitial microdeletion spanning approximately 2.9 Mb in the 5q12 region. The microdeletion is associated with epilepsy in the father and 2 siblings (a boy and a girl). So far, this is the first report in which a familial microdeletion 5q12 manifests in epilepsy. We suggest that this familial microdeletion could delineate a locus for susceptibility to epilepsy.

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“…Several endogenous neuropeptides, such as NPY (YPSKP‐DNPGEDAPAEDMARYYSALRHYINLITRQRY‐NH 2 ), NT (ZLY‐ENKPRRPYIL), and GAL (GWTLNSAGYLLGPHAVGNHRSFS DKNGLTS‐NH 2 ), possess both antiepileptic and antinociceptive properties mediated by their respective receptors in the CNS1–3. These neuropeptides show promise as potential first‐in‐class therapeutics for the treatment of epilepsy and/or pain.…”

Section: Introductionmentioning

confidence: 99%

“…This 13‐residue peptide has been widely studied for its antinociceptive properties, shown to be mediated through two receptor subtypes, NTR‐1 and NTR‐219, 20. More recently, Lee and coworkers demonstrated the ability of NT and its glycosylated analogs to suppress epileptic seizures in the brain with remarkable potency (for NT, ED 50 = 0.001 nmol in the 6 Hz mouse model of epilepsy, intracerebroventricular injection)2. SAR studies have revealed that the C ‐terminal portion of the peptide, NT (8–13), is sufficient for receptor activation21, 22.…”

Section: Introductionmentioning

confidence: 99%

Introduction of lipidization–cationization motifs affords systemically bioavailable neuropeptide Y and neurotensin analogs with anticonvulsant activities

Green

White

McDougle

et al. 2010

Journal of Peptide Science

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The neuropeptides galanin (GAL), neuropeptide Y (NPY) or neurotensin (NT) exhibit anticonvulsant activities mediated by their respective receptors in the brain. To transform these peptides into potential neurotherapeutics, their systemic bioavailability and metabolic stability must be improved. Our recent studies with GAL analogs suggested that an introduction of lipoamino acids in the context of oligo-Lys residues (lipidization-cationization motif) significantly increases their penetration into the brain, yielding potent antiepileptic compounds. Here, we describe an extension of this strategy to NPY and NT. Rationally designed analogs of NPY and NT containing the lipidization-cationization motif were chemically synthesized and their physicochemical and pharmacological properties were characterized. The analogs NPY-BBB2 and NT-BBB1 exhibited increased serum stability, possessed log D > 1.1, retained high affinities toward their native receptors and produced potent antiseizure activities in animal models of epilepsy following intraperitoneal administration. Our results suggest that the combination of lipidization and cationization may be an effective strategy for improving systemic bioavailability and metabolic stability of various neuroactive peptides.

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Glycosylated Neurotensin Analogues Exhibit Sub‐picomolar Anticonvulsant Potency in a Pharmacoresistant Model of Epilepsy

Cited by 29 publications

References 38 publications

Converting Peptides into Drug Leads by Lipidation

Converting Peptides into Drug Leads by Lipidation

Familial 5q12.3 Microdeletion: Evidence for a Locus Associated with Epilepsy

Introduction of lipidization–cationization motifs affords systemically bioavailable neuropeptide Y and neurotensin analogs with anticonvulsant activities

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