Oral Delivery of Peptide Drugs

Hamman, Josias H.; Enslin, Gill; Kotzé, A.F

doi:10.2165/00063030-200519030-00003

Cited by 395 publications

(128 citation statements)

References 97 publications

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“…Nanoparticles, a more recently developed technology, have also been highly successful in delivering systemically administered peptides into brain tissue at pharmacologically relevant concentrations (33). Efforts are also being made to improve the oral delivery of peptides to increase their marketability as therapeutic agents (34).…”

Section: Discussionmentioning

confidence: 99%

Identification of Novel Specific Allosteric Modulators of the Glycine Receptor Using Phage Display

Tipps

Lawshe

Ellington

et al. 2010

Journal of Biological Chemistry

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The glycine receptor (GlyR) is a member of the Cys-loop superfamily of ligand-gated ion channels and the major mediator of inhibitory neurotransmission in the spinal cord and brainstem. Many allosteric modulators affect the functioning of members of this superfamily, with some such as benzodiazepines showing great specificity and others such as zinc, alcohols, and volatile anesthetics acting on multiple members. To date, no potent and efficacious allosteric modulator acting specifically at the GlyR has been identified, hindering both experimental characterization of the receptor and development of GlyR-related therapeutics. We used phage display to identify novel peptides that specifically modulate GlyR function. Peptide D12-116 markedly enhanced GlyR currents at low micromolar concentrations but had no effects on the closely related ␥-aminobutyric acid type A receptors. This approach can readily be adapted for use with other channels that currently lack specific allosteric modulators.The glycine receptor (GlyR) 2 is a member of the Cys-loop superfamily of ligand-gated ion channels, including also the ␥-aminobutyric acid type A (GABA A ) and serotonin-3 receptors. They share a number of structural features, including ligand-binding sites in the extracellular N-terminal domain and a transmembrane domain consisting of four segments, with a large intracellular loop connecting segments 3 and 4. Individual channels consist of five subunits co-localized with the transmembrane domain 2 segment of each subunit lining the anionconducting pore (1, 2). Two classes of GlyR subunits have been identified: the ␣ subunits, of which there are four subtypes, and a single ␤ subunit (3). Most native GlyRs in adult animals consist of heteromeric ␣1␤ subunits, although homomeric ␣2 receptors are the predominant form found prenatally (4). GlyRs constitute the major inhibitory neurotransmitter receptor system in the brainstem and spinal cord (5), where they are thought to play a role in the modulation of pain signals and in the effects of volatile anesthetics (1). Some GlyR mutations result in the startle disorder hyperekplexia. GlyRs are also found throughout the brain, including the thalamus, hippocampus, and nucleus accumbens, where they were recently shown to be involved in the reinforcing properties of ethanol (6). The GlyR is only one of multiple ion channels and receptors thought to play a role in pain perception and alcohol and volatile anesthetic effects and in determining the state of neuronal excitability. The isolation of the role of the GlyR is hindered by the fact that, to date, no potent and efficacious allosteric modulator acting specifically at the GlyR has been identified. Phage display involves the expression of a random library of peptides on the coat proteins of bacteriophage. This method has long been used to identify peptides that can bind with high affinity to selected targets and to aid in identifying binding motifs (7). We combined phage display technology with standard electrophysiological testing to identi...

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Section: Discussionmentioning

confidence: 99%

Identification of Novel Specific Allosteric Modulators of the Glycine Receptor Using Phage Display

Tipps

Lawshe

Ellington

et al. 2010

Journal of Biological Chemistry

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“…Although the most recent strategies on peptidic prodrugs have mainly focused on the cyclization of the peptide backbone, [25] we cannot exploit such a strategy because the commonly used linkers (e.g., phenylpropionic acid derivatives) are inadequate to balance the marked polarity of d-CAR, and thus we would have to use very bulky linkers which would hamper the enzymatic hydrolysis. Moreover, the cyclization is synthetically feasible for longer peptides, whereas short dipeptides tend to polymerize rather than undergo cyclization.…”

Section: Design and Synthesismentioning

confidence: 99%

Design, Synthesis, ADME Properties, and Pharmacological Activities of β‐Alanyl‐D‐histidine (D‐Carnosine) Prodrugs with Improved Bioavailability

et al. 2011

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β-Alanyl-D-histidine (D-CAR, the enantiomer of the natural dipeptide carnosine) is a selective and potent sequestering agent of reactive carbonyl species (RCS) that is stable against carnosinase, but is poorly absorbed in the gastrointestinal tract. Herein we report a drug discovery approach aimed at increasing the oral bioavailability of D-CAR. In our study we designed, synthesized, and evaluated a series of novel lipophilic D-CAR prodrugs. The considered prodrugs can be divided into two categories: 1) derivatives with both terminal groups modified, in which the carboxyl terminus is always esterified while the amino terminus is protected by an amidic (N-acetyl derivatives) or a carbamate (ethyloxy or benzyloxy derivatives) function; 2) derivatives with only one terminus modified, which can be alkyl esters as well as amidic or carbamate derivatives. The prodrugs were designed considering their expected lipophilicity and their hydrolysis predicted by docking simulations on the most important human carboxylesterase (hCES1). The stability and metabolic profile of the prodrugs were studied by incubating them with rat and human serum and liver fractions. The octyl ester of D-CAR (compound 13) was chosen as a candidate for further pharmacological studies due to its rapid hydrolysis to the bioactive metabolite in vitro. Pharmacokinetic studies in rats confirmed the in vitro data and demonstrated that the oral bioavailability of D-CAR is increased 2.6-fold if given as an octyl ester relative to D-CAR. Compound 13 was then found to dose-dependently (at daily doses of 3 and 30 mg kg(-1) equivalent of D-CAR) decrease the development of hypertension and dyslipidemia, to restore renal functions of Zucker fa/fa obese rats, and to inhibit the carbonylation process (AGEs and pentosidine) as well as oxidative stress (urinary 8-epi-prostaglandin F2α and nitrotyrosine). A plausible mechanism underlying the protective effects of 13 is RCS sequestration, as evidenced by the significant increase in the level of adduct between CAR and 4-hydroxy-trans-2-nonenal (HNE, the main RCS generated by lipid oxidation) in the urine of treated animals.

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“…A major concern for the use of peptides as drug candidates is their short intracellular half-life (57). However, high activity, high specificity, high potency, low toxicity, low drug-drug interaction, low tissue accumulation, recent improvements in formulation, and manufacturing technology are increasingly bringing peptides into the drug market (58,59).…”

Section: Discussionmentioning

confidence: 99%

Basic Tetrapeptides as Potent Intracellular Inhibitors of Type A Botulinum Neurotoxin Protease Activity

Hale

Oyler

Swaminathan

et al. 2011

Journal of Biological Chemistry

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Botulinum neurotoxins (BoNT) are the most potent of all toxins that cause flaccid muscle paralysis leading to death. They are also potential biothreat agents. A systematic investigation of various short peptide inhibitors of the BoNT protease domain with a 17-residue peptide substrate led to argininearginine-glycine-cysteine having a basic tetrapeptide structure as the most potent inhibitor. When assayed in the presence of dithiothreitol (DTT), the inhibitory effect was drastically reduced. Replacing the terminal cysteine with one hydrophobic residue eliminated the DTT effect but with two hydrophobic residues made the pentapeptide a poor inhibitor. Replacing the first arginine with cysteine or adding an additional cysteine at the N terminus did not improve inhibition. When assessed using mouse brain lysates, the tetrapeptides also inhibited BoNT/A cleavage of the endogenous SNAP-25. The peptides penetrated the neuronal cell lines, N2A and BE(2)-M17, without adversely affecting metabolic functions as measured by ATP production and P-38 phosphorylation. Biological activity of the peptides persisted within cultured chick motor neurons and rat and mouse cerebellar neurons for more than 40 h and inhibited BoNT/A protease action inside the neurons in a dose-and time-dependent fashion. Our results define a tetrapeptide as the smallest peptide inhibitor in the backdrop of a large substrate protein of 200؉ amino acids having multiple interaction regions with its cognate enzyme. The inhibitors should also be valuable candidates for drug development. Botulinum neurotoxins (BoNT)2 produced by strains of Clostridium botulinum, are the deadliest of all toxins (1). There are seven distinct serotypes, A-F, of which BoNT/A afflicts humans most frequently. The latter is also the most stable in neurons causing long term paralysis. The toxins are 150-kDa proteins comprising a 50-kDa protease light chain (LC) and a 100-kDa binding-translocating heavy chain. Upon entry to animal body, the toxins travel to peripheral neurons where heavy chain binds and translocates LC into the neurons. After dissociating from the heavy chain (2), LC cleaves at specific sites on one of three SNARE (soluble N-ethylmaleimide factor attachment protein receptor) proteins, thereby blocking exocytosis of acetylcholine into the neuromuscular junction and causing muscle paralysis. The paralysis prevents normal respiration and eventually leads to death of the animal. One of the hallmark features of BoNT/A intoxication is the extreme persistence of symptoms with neuroparalysis often lasting in excess of 3-4 months. Currently, there is no effective postexposure therapeutic available against botulism. Because of extreme toxicity, BoNT is a potential biowarfare and bioterrorism threat, and both Centers for Disease Control and Prevention and the United States Department of Agriculture have placed it as a category A threat agent.The substrate for BoNT/A is an ϳ210-residue SNAP-25 depending on species. Schmidt and Bostian (3) reported that unlike most other proteases,...

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Oral Delivery of Peptide Drugs

Cited by 395 publications

References 97 publications

Identification of Novel Specific Allosteric Modulators of the Glycine Receptor Using Phage Display

Identification of Novel Specific Allosteric Modulators of the Glycine Receptor Using Phage Display

Design, Synthesis, ADME Properties, and Pharmacological Activities of β‐Alanyl‐D‐histidine (D‐Carnosine) Prodrugs with Improved Bioavailability

Basic Tetrapeptides as Potent Intracellular Inhibitors of Type A Botulinum Neurotoxin Protease Activity

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