Stability, Permeability and Growth-Inhibitory Properties of Gonadotropin-Releasing Hormone Liposaccharides

Goodwin, Daryn; Varamini, Pegah; Simerská, Pavla; Tóth, István

doi:10.1007/s11095-014-1558-1

Cited by 10 publications

(8 citation statements)

References 50 publications

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“…; Goodwin et al. ). Although the effects of lipidation of a parent molecule on blood–brain barrier (BBB) penetration have not been documented, hydrophobic small molecules with a higher log‐ P values show better penetration across the BBB compared to their parental hydrophilic congeners (Egleton and Davis ).…”

Section: Introductionmentioning

confidence: 99%

Structure-specific effects of lipidated oxytocin analogs on intracellular calcium levels, parental behavior, and oxytocin concentrations in the plasma and cerebrospinal fluid in mice

Cherepanov

Yokoyama

Mizuno

et al. 2017

Pharmacol Res Perspect

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Oxytocin (OT) is a neuroendocrine nonapeptide that plays an important role in social memory and behavior. Nasal administration of OT has been shown to improve trust in healthy humans and social interaction in autistic subjects in some clinical trials. As a central nervous system (CNS) drug, however, OT has two unfavorable characteristics: OT is short‐acting and shows poor permeability across the blood–brain barrier, because it exists in charged form in the plasma and has short half‐life. To overcome these drawbacks, an analog with long‐lasting effects is required. We previously synthesized the analog, lipo‐oxytocin‐1 (LOT‐1), in which two palmitoyl groups are conjugated to the cysteine and tyrosine residues. In this study, we synthesized and evaluated the analogs lipo‐oxytocin‐2 (LOT‐2) and lipo‐oxytocin‐3 (LOT‐3), which feature the conjugation of one palmitoyl group at the cysteine and tyrosine residues, respectively. In human embryonic kidney‐293 cells overexpressing human OT receptors, these three LOTs demonstrated comparably weak effects on the elevation of intracellular free calcium concentrations after OT receptor activation, compared to the effects of OT. The three LOTs and OT exhibited different time‐dependent effects on recovery from impaired pup retrieval behavior in sires of CD38‐knockout mice. Sires treated with LOT‐1 showed the strongest effect, whereas others had no or little effects at 24 h after injection. These results indicated that LOTs have structure‐specific agonistic effects, and suggest that lipidation of OT might have therapeutic benefits for social impairment.

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Section: Introductionmentioning

confidence: 99%

Structure-specific effects of lipidated oxytocin analogs on intracellular calcium levels, parental behavior, and oxytocin concentrations in the plasma and cerebrospinal fluid in mice

Cherepanov

Yokoyama

Mizuno

et al. 2017

Pharmacol Res Perspect

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“…The lipopeptide conjugates enhance the membranelike characteristics of the peptides due to their lipid nature 2 . Enhancement of metabolic stability and membrane permeability at the same time could considerably contribute to improvement in the bioavailability of peptides 3,4 .…”

Section: Introductionmentioning

confidence: 99%

“…We have previously shown that lipid-modified luteinizing hormone-releasing hormone (LHRH, also known as gonadotropin-releasing hormone, GnRH) peptides served as effective prodrugs for the release of the parent peptide 4,8 . It was shown that one stereoisomer of the lipid was cleaved very rapidly, providing a large amount of the parent peptide while the opposite stereoisomer was cleaved much more slowly and providing prolonged increase in the LHRH peptide concentration 8 .…”

Section: Introductionmentioning

confidence: 99%

A study on liposomal encapsulation of a lipophilic prodrug of LHRH

Pignatello

Musumeci

Graziano

et al. 2015

Pharmaceutical Development and Technology

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This study aimed at evaluating whether derivatization of luteinizing hormone-releasing hormone (LHRH) peptide with an amphiphilic lipoamino acid moiety could allow, along with other technological and/or pharmacokinetic advantages, to improve its encapsulation in liposomes, potentially driving its further body distribution and cellular uptake. Experimental data confirmed that a lipophilic derivative of LHRH was efficiently incorporated in various liposomal systems, differing in lipid composition and surface charge, and obtained using different methods of production. Incubation of liposomes, loaded with a fluorescent derivative of the LHRH prodrug, with NCTC keratinocytes or Caco-2 cell cultures showed that the carriers can be rapidly internalized. Conversely, the internalization of the free prodrug occurred only at very high concentrations.

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“…Thus, the nasal route might potentiate the accumulation of the brain permeable peptide with a long half-life in circulation, resulting in brain levels that reach 1-2% of the dose administered. The diffusion of therapeutic peptides (<10 kDa) into the extracellular brain parenchyma, such as that described here, is not restricted significantly when compared to that of larger neurotrophic factors like neurotrophins, PDGF (platelet-derived growth factor) and CNTF (ciliary neurotrophic factor) which approach the dimensions of the extracellular space (15-20 nm in diameter) (39). The clearance of the peptides in the target organ is also an essential feature, as this will permit the degradation of the therapeutic peptides into elements that are naturally present in the brain parenchyma (40).…”

Section: Discussionmentioning

confidence: 87%

Preformulation Studies of a Stable PTEN-PDZ Lipopeptide Able to Cross an In Vitro Blood-Brain-Barrier Model as a Potential Therapy for Alzheimer’s Disease

et al. 2020

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Purpose Amyloid β (Aβ) drives the accumulation of excess Phosphatase and Tensin Homolog Deleted on Chromosome 10 (PTEN) at synapses, inducing synaptic depression and perturbing memory. This recruitment of PTEN to synapses in response to Aβ drives its interaction with PSD95/Disc large/Zonula occludens-1 (PDZ) proteins and, indeed, we previously showed that an oligo lipopeptide (PTEN-PDZ) capable of blocking such PTEN:PDZ interactions rescues the synaptic and cognitive deficits in a mouse model of Alzheimer’s disease. Hence, the PTEN:PDZ interaction appears to be crucial for Aβ-induced synaptic and cognitive impairment. Here we have evaluated the feasibility of using PTEN-PDZ lipopeptides based on the human/mouse PTEN C-terminal sequence, testing their stability in biological fluids, their cytotoxicity, their ability to self-assemble and their in vitro blood-brain barrier (BBB) permeability. Myristoyl or Lauryl tails were added to the peptides to enhance their cell permeability. Methods Lipopeptides self assembly was assessed using electron microscopy and the thioflavin T assay. Stability studies in mouse plasma (50%), intestinal washing, brain and liver homogenates as well as permeability studies across an all human 2D blood-brain barrier model prepared with human cerebral endothelial cells (hCMEC/D3) and human astrocytes (SC-1800) were undertaken. Results The mouse lauryl peptide displayed enhanced overall stability in plasma, ensuring a longer half-life in circulation that meant there were larger amounts available for transport across the BBB (Papp0-4h: 6.28 ± 1.85 × 10−6 cm s−1). Conclusion This increased availability, coupled to adequate BBB permeability, makes this peptide a good candidate for therapeutic parenteral (intravenous, intramuscular) administration and nose-to-brain delivery. Graphical Abstract

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Stability, Permeability and Growth-Inhibitory Properties of Gonadotropin-Releasing Hormone Liposaccharides

Abstract: These results indicated lipidation and glycosylation improves the druggability of GnRH and could lead to an increased direct antitumour activity in some hormone dependent and independent reproductive cancers.

Cited by 10 publications

References 50 publications

Structure-specific effects of lipidated oxytocin analogs on intracellular calcium levels, parental behavior, and oxytocin concentrations in the plasma and cerebrospinal fluid in mice

Structure-specific effects of lipidated oxytocin analogs on intracellular calcium levels, parental behavior, and oxytocin concentrations in the plasma and cerebrospinal fluid in mice

A study on liposomal encapsulation of a lipophilic prodrug of LHRH

Preformulation Studies of a Stable PTEN-PDZ Lipopeptide Able to Cross an In Vitro Blood-Brain-Barrier Model as a Potential Therapy for Alzheimer’s Disease

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