Glycopeptide drugs: A pharmacological dimension between “Small Molecules” and “Biologics”

Apostol, Christopher; Hay, Meredith; Polt, Robin

doi:10.1016/j.peptides.2020.170369

Cited by 38 publications

(37 citation statements)

References 142 publications

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“…Polt and coworkers suggested that glycopeptides have a biousian character (two essences), referring to the two different conformational states a biousian glycopeptides can adopt in the aqueous bulk compartment and when bound to the membrane. As glycopeptides have relatively lipophilic backbones and hydrophilic sugar moieties, this allows a glycopeptide to interact with both the membrane surface and aqueous compartment in a “hopping” motion, which promotes transport of the drug throughout the body in vivo and improvs the bioavailability [ 67 , 68 , 69 , 70 ]. Lactomorphin was found to be freely soluble in water, NS, and PBS with an aqueous solubility of >100 mg/mL.…”

Section: Discussionmentioning

confidence: 99%

Organic Solution Advanced Spray-Dried Microparticulate/Nanoparticulate Dry Powders of Lactomorphin for Respiratory Delivery: Physicochemical Characterization, In Vitro Aerosol Dispersion, and Cellular Studies

et al. 2020

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The purpose of this study was to formulate Lactomorphin (MMP2200) in its pure state as spray-dried(SD) powders, and with the excipient Trehalose as co-spray-dried(co-SD) powders; for intranasal and deep lung administration with Dry Powder Inhalers (DPI). Lactomorphin is a glycopeptide which was developed for the control of moderate to severe pain. Particles were rationally designed and produced by advanced spray drying particle engineering in a closed mode from a dilute organic solution. Comprehensive physicochemical characterization using different analytical techniques was carried out to analyze the particle size, particle morphology, particle surface morphology, solid-state transitions, crystallinity/non-crystallinity, and residual water content. The particle chemical composition was confirmed using attenuated total reflectance-Fourier-transform infrared (ATR-FTIR), and Confocal Raman Microscopy (CRM) confirmed the particles’ chemical homogeneity. The solubility and Partition coefficient (LogP) of Lactomorphin were determined by the analytical and computational methodology and revealed the hydrophilicity of Lactomorphin. A thermal degradation study was performed by exposing samples of solid-state Lactomorphin to a high temperature (62 °C) combined with zero relative humidity (RH) and to a high temperature (62 °C) combined with a high RH (75%) to evaluate the stability of Lactomorphin under these two different conditions. The solid-state processed particles exhibited excellent aerosol dispersion performance with an FDA-approved human DPI device to reach lower airways. The cell viability resazurin assay showed that Lactomorphin is safe up to 1000 μg/mL on nasal epithelium cells, lung cells, endothelial, and astrocyte brain cells.

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Section: Discussionmentioning

confidence: 99%

Organic Solution Advanced Spray-Dried Microparticulate/Nanoparticulate Dry Powders of Lactomorphin for Respiratory Delivery: Physicochemical Characterization, In Vitro Aerosol Dispersion, and Cellular Studies

et al. 2020

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“…The peptides and glycopeptides were prepared in the Polt Laboratory using Fmocprotection (fluorenylmethoxycarbonyl protecting group) and solid-phase synthesis, similar to previously published methods [53,54]. The native deltorphin sequence YaFEVVG-CONH2, discovered by Mignogna, et al [55], was modified by the addition of a carbohydrate, and minor modification of the lipophilic valine residues (see Table 1).…”

Section: Synthesis Of Bbi-11008mentioning

confidence: 99%

The Delta-Specific Opioid Glycopeptide BBI-11008: CNS Penetration and Behavioral Analysis in a Preclinical Model of Levodopa-Induced Dyskinesia

Bartlett

Mabrouk

Szabó

et al. 2020

IJMS

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In previous work we evaluated an opioid glycopeptide with mixed μ/δ-opioid receptor agonism that was a congener of leu-enkephalin, MMP-2200. The glycopeptide analogue showed penetration of the blood–brain barrier (BBB) after systemic administration to rats, as well as profound central effects in models of Parkinson’s disease (PD) and levodopa (L-DOPA)-induced dyskinesia (LID). In the present study, we tested the glycopeptide BBI-11008 with selective δ-opioid receptor agonism, an analogue of deltorphin, a peptide secreted from the skin of frogs (genus Phyllomedusa). We tested BBI-11008 for BBB-penetration after intraperitoneal (i.p.) injection and evaluated effects in LID rats. BBI-11008 (10 mg/kg) demonstrated good CNS-penetrance as shown by microdialysis and mass spectrometric analysis, with peak concentration levels of 150 pM in the striatum. While BBI-11008 at both 10 and 20 mg/kg produced no effect on levodopa-induced limb, axial and oral (LAO) abnormal involuntary movements (AIMs), it reduced the levodopa-induced locomotor AIMs by 50% after systemic injection. The N-methyl-D-aspartate receptor antagonist MK-801 reduced levodopa-induced LAO AIMs, but worsened PD symptoms in this model. Co-administration of MMP-2200 had been shown prior to block the MK-801-induced pro-Parkinsonian activity. Interestingly, BBI-11008 was not able to block the pro-Parkinsonian effect of MK-801 in the LID model, further indicating that a balance of mu- and delta-opioid agonism is required for this modulation. In summary, this study illustrates another example of meaningful BBB-penetration of a glycopeptide analogue of a peptide to achieve a central behavioral effect, providing additional evidence for the glycosylation technique as a method to harness therapeutic potential of peptides.

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“…[65] Attachment of sugar moieties to various peptides, including opioids can cause important changes in their native conformation, stability and activity. [66] To examine if the biological activity of the N/OFQ could be modulated by glycosylation and if such effect could be conformationally related, three N/OFQ glycopeptide analogs (Figure 1) were synthesized. [67] Two obvious Oglycosylation sites in the N/OFQ sequence are hydroxyl groups of Thr 5 and Ser 10 .…”

Section: Agonist Ligandsmentioning

confidence: 99%

Potential of Nociceptin/Orphanin FQ Peptide Analogs for Drug Development

Wtorek

Janecka

2020

Chemistry & Biodiversity

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Nociceptin receptor (NOP) belongs to the family of opioid receptors but was discovered and characterized much later than the so called classical opioid receptors, μ, δ and к (or MOP, DOP and KOP, resp.). Nociceptin/ orphanin FQ (N/OFQ) is the endogenous ligand of this receptor and it controls numerous important functions in the central nervous system and in the periphery, so its analogs may be developed as innovative drugs for the treatment of a variety of conditions and pathological states. Availability of potent and selective ligands with high affinity to NOP receptor is essential to fully understand the role of NOP-N/OFQ system in the body, which in turn may lead to designing novel therapeutics. Here, we have focused on reviewing the structure of potent peptidebased agonists, antagonists, biased analogs and bivalent ligands that target NOP receptor.

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Glycopeptide drugs: A pharmacological dimension between “Small Molecules” and “Biologics”

Cited by 38 publications

References 142 publications

Organic Solution Advanced Spray-Dried Microparticulate/Nanoparticulate Dry Powders of Lactomorphin for Respiratory Delivery: Physicochemical Characterization, In Vitro Aerosol Dispersion, and Cellular Studies

Organic Solution Advanced Spray-Dried Microparticulate/Nanoparticulate Dry Powders of Lactomorphin for Respiratory Delivery: Physicochemical Characterization, In Vitro Aerosol Dispersion, and Cellular Studies

The Delta-Specific Opioid Glycopeptide BBI-11008: CNS Penetration and Behavioral Analysis in a Preclinical Model of Levodopa-Induced Dyskinesia

Potential of Nociceptin/Orphanin FQ Peptide Analogs for Drug Development

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