Peptide drugs to target G protein-coupled receptors

doi:10.1016/j.tips.2010.06.003

Trends in Pharmacological Sciences

Volume 31, Issue 9, September 2010, Pages 434-441

https://doi.org/10.1016/j.tips.2010.06.003 Get rights and content

Major indications for use of peptide-based therapeutics include endocrine functions (especially diabetes mellitus and obesity), infectious diseases, and cancer. Whereas some peptide pharmaceuticals are drugs, acting as agonists or antagonists to directly treat cancer, others (including peptide diagnostics and tumour-targeting pharmaceuticals) use peptides to ‘shuttle’ a chemotherapeutic agent or a tracer to the tumour and allow sensitive imaging or targeted therapy. Significant progress has been made in the last few years to overcome disadvantages in peptide design such as short half-life, fast proteolytic cleavage, and low oral bioavailability. These advances include peptide PEGylation, lipidisation or multimerisation; the introduction of peptidomimetic elements into the sequences; and innovative uptake strategies such as liposomal, capsule or subcutaneous formulations. This review focuses on peptides targeting G protein-coupled receptors that are promising drug candidates or that have recently entered the pharmaceutical market.

Introduction

The several hundred G protein-coupled receptors (GPCRs) that are expressed in humans are subdivided into three major classes (A, B, C) according to their structure and binding mode. Many GPCRs bind peptide hormones or small protein ligands, e.g. all class-B GPCRs and most hormone-binding class-A receptors [1]. Peptide ligands can vary from 3 amino acids (e.g. thyroid-stimulating hormone (TSH)) to polypeptides of ≥60 residues. Many peptides act as hormones, neurotransmitters or neuromodulaters, so peptides are becoming increasingly interesting as drug candidates [2]. Synthesis strategies have been worked out that allow the production of large quantities and marketing of peptide drugs. Conversely, their low toxicity and the non-toxic metabolic cleavage products of peptides suggests they are safe drugs [3]. Disease indications for peptides that are currently being studied in phase I trials include cancer (30%), metabolic diseases (20%), inflammation (13%) and virology (5%). The use of peptides in the central nervous system (12%) is also being explored as therapy and as a diagnostic tool (20%) [4]. In spite of these successes, peptide engineering must be conducted to overcome problems such as proteolytic degradation, fast clearance in the body, low solubility in water, and the immunogenicity of peptide drugs. However, general routes are now available that can be adapted to the distinct peptide and which are dependent upon its sequence and required application. Peptides that target obesity must have few side effects, no immunogenicity, and increased stability. Peptides against cancer require high efficiency, selectivity and reduced proteolytic cleavage.

This review describes the impact of peptide drugs targeting GPCRs in the immune system. In particular, we focus on peptides that can inhibit HIV entry (and therefore prevent the onset of AIDS) and for the treatment of inflammation. Furthermore, we focus on the high potential of peptides for GPCRs on the treatment of obesity, an increasing problem in the Western world. Peptide drugs within the large field of cancer treatment and diagnosis are also discussed.

Section snippets

Peptide drugs that target the immune system

Peptide drugs that target the immune system are used to treat infectious diseases or inflammation. The main reason for this is the high density of GPCRs on immune cells that are activated by small peptides or chemokines. Peptides directed against infectious diseases have not been applied until recently. This has changed with the novel generation of anti-HIV/AIDS drugs that interfere directly with virus entry. It has been shown that HIV requires CC chemokine receptor (CCR)5 or CXC chemokine

Peptides that modulate endocrine functions

Worldwide, 1.1 billion adults and 10% of children are classified as ‘overweight’ or ‘obese’, and obesity is considered to be one of the major health risks in the twenty-first century, particularly in the Western world [20]. The main problem is not the abnormal gain of fat per se, but its association with several comorbidities that include cardiovascular disease, cancer and diabetes mellitua. These disorders lead to a significant reduction in life expectancy and a dramatic increase in health

Peptides that target cancer

Many tumour cells express or overexpress peptide GPCRs compared with the original tissue they are derived from. This difference in expression is exploited in direct or indirect therapeutic concepts. In direct approaches, the activity of the endogenous peptide hormone is used and blocked or stimulated by the peptide drug. Two hormone cascades are currently targeted with peptide drugs: the somatostatin (SST)/growth hormone (GH) cascade, and the gonadotropin releasing hormone (GnRH)/luteinizing

From biologically active peptides to peptide drugs

In the past, the utility of peptides as drugs was controversial due to their proteolytic susceptibility, their limited bioavailability, and oral formulation. Significant advances have been achieved by improvement of the synthesis strategies (Box 1) using pegylated variants, lipidated peptides with fatty-acid acylation or nanoparticle-based delivery systems (e.g. liposomes). PEGylation has gained significant attention during the last years, with Pegasys [59] and Peg-intron [60], two interferon-α

Conclusion

More than 70 therapeutic peptides are on the market; >150 peptides are in clinical development, with several in late-phase clinical trials (Table 2), and >400 in advanced pre-clinical studies. More than 100 pharmaceutical biotech companies are working on the development of bioactive peptides, many of which target GPCRs. Peptide drugs can target metabolic diseases which require few side effects to ensure compliance and high safety levels because the drug has to be taken for several years.

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The neuropeptide Y (NPY) Y₄ receptor is a G protein coupled receptor, which is targeted by pancreatic polypeptide, a homologue of NPY. Selective Y₄R agonists were suggested as potential therapeutics for the treatment of obesity. Highly potent dimeric peptidic Y₄R agonists, constituting two pentapeptide moieties connected through an aliphatic linker, represent an interesting class of Y₄R ligands. Based on this compound class, photoresponsive Y₄R ligands, containing an azobenzene, azopyrazole, diethienylethene or a fulgimide chromophore were prepared to explore structural requirements of such Y₄R agonists on Y₄R binding. The synthesized Y₄R ligands, containing a non-aliphatic rigid photochromic linker, switch reversibly in aqueous buffer and exhibited high Y₄R affinity throughout. This demonstrated that the replacement of the highly flexible aliphatic linker by a considerably less flexible photochromic linker was well tolerated with respect to Y₄R binding. Differences in Y₄R affinity and activity between the individual photoisomers (varying in spatial orientation and flexibility) were marginal suggesting that the linking element in the dimeric ligands is less critical for the adaptation of high-affinity binding modes at the receptor.
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Lipidation is a powerful strategy to improve the stability in vivo of peptide drugs. Attachment of a lipid chain to a hydrophilic peptide leads to amphiphilicity and the potential for surfactant-like self-assembly. Here, the self-assembly and conformation of three lipidated derivatives of the gastrointestinal peptide hormone PYY_3–36 is examined using a comprehensive range of spectroscopic, scattering, and electron microscopy methods and compared to those of the parent PYY_3–36 peptide. The peptides are lipidated at Ser(11), Arg(17), or Arg(23) in the peptide; the former is within the β-turn domain (based on the published solution NMR structure), and the latter two are both within the α-helical domain. We show that it is possible to access a remarkable diversity of nanostructures ranging from micelles to nanotapes and fibrillar hydrogels by control of assembly conditions (concentration, pH, and temperature). All of the lipopeptides self-assemble above a critical aggregation concentration (cac), determined through pyrene fluorescence probe measurements, and they all have predominantly α-helical secondary structure at their native pH. The pH and temperature dependence of the α-helical conformation were probed via circular dichroism spectroscopy experiments. Lipidation was found to provide enhanced stability against changes in temperature and pH. The self-assembled structures were investigated using small-angle X-ray scattering (SAXS) and cryogenic transmission electron microscopy (cryo-TEM). Distinct differences in nanostructure were observed for lipidated and unlipidated peptides, also depending on the position of lipidation. Remarkably, micelles containing lipopeptides with α-helical peptide conformation were observed. Gelation was observed at higher concentrations in certain pH intervals for the lipidated peptides, but not for unlipidated PYY_3–36. Thus, lipidation, in addition to enhancing stability against pH and temperature variation, also provides a route to prepare PYY peptide hydrogels. These findings provide important insights into the control of PYY_3–36 conformation and aggregation by lipidation, relevant to the development of future therapeutics based on this peptide hormone, for example, in treatments for obesity.
Chiral β<inf>3</inf>-isocyanopropionates for multicomponent synthesis of peptides and depsipeptides containing a β-amino acid fragment
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An efficient three-step synthesis of a novel family of enantiomerically pure isocyanides derived from β₃-isocyanopropionic acids was elaborated. Easily available N-formylated α-amino acids were used as starting materials towards this aim. The 3-step sequence (Arndt–Eistert reaction–Wolff rearrangement–dehydration) resulted in target isonitriles in good yields (up to 97%). As a result a new family of isocyanides bearing a fragment of β₃-amino acids with different functional groups (amides, esters and short peptides) was obtained. It was demonstrated that these new isonitriles can be used in the Ugi and Passerini reactions to prepare short peptides and depsipeptides having a β-amino acid fragment incorporated.
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(Neuro)peptides are small messenger molecules that are derived from larger, inactive precursor proteins by the highly controlled action of processing enzymes. These biologically active peptides can be found in all metazoan species where they orchestrate a wide variety of physiological processes. Obviously, detailed knowledge on the actual peptide sequences, including the potential existence of truncated versions or presence of post-translation modifications, is of high importance when studying their function. A peptidomics approach therefore aims to identify and characterize the endogenously present peptide complement of a defined tissue or organism using liquid chromatography and mass spectrometry. While the zebrafish Danio rerio is considered as an important aquatic model for medical research, neuroscience, development and ecotoxicology, very little is known about their peptidergic signaling cascades. We therefore set out to biochemically characterize endogenously present (neuro)peptides from the zebrafish brain. This peptidomics setup yielded > 60 different peptides in addition to various truncated versions.
Though the zebrafish is a well-established model organism to study vertebrate biology and gene functions in either a medical or (eco)toxicological context, very little knowledge about neuropeptidergic signaling cascades is available. We therefore set out to characterize endogenously present peptides from the zebrafish brain using a peptidomics setup yielding a total number of 105 peptide identifications. To our knowledge, it is the first attempt to biochemically isolate and characterize neuropeptides from a fish species in a high-throughput manner. This archive of identified endogenous peptides is likely to aid further functional elucidation of defined neuropeptidergic signaling systems (e.g. characterization of cognate G-protein coupled receptors). Furthermore, our methodology allows studying the changes in peptide expression in response to changes in the organism or the environment using differential peptidomics.
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Citation Excerpt :
They can be highly specific and potent in their pharmacological effects, but suffer from limited modes of delivery, poor bioavailability and rapid clearance [1]. Not surprisingly, considerable effort has been made to formulate peptide-based drugs that enhance their availability or increase their biological stability [2]. This has led to a rapid growth in recent approvals of peptides as therapeutics [3].
Thermoplastic polyurethanes (TPUs) are widely used in biomedical applications due to their excellent biocompatibility. Their role as matrices for the delivery of small molecule therapeutics has been widely reported. However, very little is known about the release of bioactive peptides from this class of polymers. Here, we report the release of linear and cyclic peptides from TPUs with different hard and soft segments. Solvent casting of the TPU at room temperature mixed with the different peptides resulted in reproducible efflux profiles with no evidence of drug degradation. Peptide release was dependent on the size as well as the composition of the TPU. Tecoflex 80A (T80A) showed more extensive release than ElastEon 5-325, which correlated with a degree of hydration. It was also shown that the composition of the medium influenced the rate and extent of peptide efflux. Blending the different TPUs allowed for better control of peptide efflux, especially the initial burst effect. Peptide-loaded TPU prolonged the plasma levels of the anti-inflammatory cyclic peptide PMX53, which normally has a plasma half-life of less than 30 min. Using a blend of T80A and E5-325, therapeutic plasma levels of PMX53 were observed up to 9 days following a single intraperitoneal implantation of the drug-loaded film. PMX53 released from the blended TPUs significantly inhibited B16-F10 melanoma tumor growth in mice demonstrating its bioactivity in vivo. This study provides important findings for TPU-based therapeutic peptide delivery that could improve the pharmacological utility of peptides as therapeutics.
Therapeutic peptides can be highly specific and potent pharmacological agents, but are poorly absorbed and rapidly degraded in the body. This can be overcome by using a matrix that protects the peptide in vivo and promotes its slow release so that a therapeutic effect can be achieved over days or weeks. Thermoplastic polyurethanes are a versatile family of polymers that are biocompatible and used for medical implants. Here, the release of several peptides from a range of polyurethanes was shown to depend on the type of polymer used in the polyurethane. This is the first study to examine polyurethane blends for peptide delivery and shows that the rate and extent of peptide release can be fine-tuned using different hard and soft segment mixtures in the polymer.
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Obesity is an escalating epidemic, but an effective non-invasive therapy is still scarce. For obesity treatment, anorexigenic neuropeptides are promising tools, but their delivery from the periphery to the brain is complicated by their peptide character. In order to overcome this unfavorable fact, we have applied the lipidization of neuropeptide prolactin-releasing peptide (PrRP), whose strong anorexigenic effect was demonstrated. A palmitoylated analog of human PrRP (h palm-PrRP31) was injected in free-fed Wistar rats by three routes: subcutaneous (s.c.), intraperitoneal (i.p) (both 5 mg/kg) and intravenous (i.v.) (from 0.01 to 0.5 mg/kg). We found a circulating compound in the blood after all three applications with the highest concentration after i.v. administration. This corresponds to the effect on food intake, which was also strongest after i.v. injection. Moreover, this is in agreement with the fact that the expression of c-Fos in specific brain regions involved in food intake regulation was also highest after intravenous application. Pharmacokinetic data are further supported by results obtained from dynamic light scattering and CD spectroscopy. Human palm-PrRP31 analog showed a strong tendency to micellize, and formation of aggregates suggested lower availability after i.p. or s.c. application. We have demonstrated that palm-PrRP influenced food intake even in free fed rats. Not surprisingly, the maximal effect was achieved after the intravenous application even though two orders of magnitude lower dose was used compared to both two other applications. We believe that palm-PrRP could have a potential as an antiobesity drug when its s.c. application would be improved.

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Trends in Pharmacological Sciences

ReviewPeptide drugs to target G protein-coupled receptors

Introduction

Section snippets

Peptide drugs that target the immune system

Peptides that modulate endocrine functions

Peptides that target cancer

From biologically active peptides to peptide drugs

Conclusion

Tetrahedron

J. Virol. Methods

Biochem. Pharmacol.

Am. J. Transplant.

Lancet

Curr. Opin. Pharmacol.

Gastroenterology

Trends Pharmacol. Sci.

Gastroenterology

Gastroenterology

FEBS Lett.

Peptides

Peptides

J. Urol.

Lancet

Blood

Adv. Drug Deliv. Rev.

Illuminating the life of GPCRs

Cell Commun. Signal.

Structure-activity relationship studies: methods and ligand design for G-protein coupled peptide receptors

Curr. Protein Pept. Sci.

Watching peptide drugs grow up

Chem. Eng. News

Chemokines and chemokine receptors in HIV infection: role in pathogenesis and therapeutics

J. Postgrad. Med.

Chemokine receptor antagonists: Part 1

Expert Opin. Ther. Pat.

Chemokine receptor antagonists: part 2

Expert Opin. Ther. Pat.

HIV-1 membrane fusion mechanism: structural studies of the interactions between biologically-active peptides from gp41

Biochemistry

Cost-effectiveness analysis of enfuvirtide (ENF) added to an optimized therapy compared with an optimized therapy in patients with HIV/AIDS

HIV Clin. Trials

PSC-RANTES blocks R5 human immunodeficiency virus infection of Langerhans cells isolated from individuals with a variety of CCR5 diplotypes

J. Virol.

Cyclosporin H, Boc-MLF and Boc-FLFLF are antagonists that preferentially inhibit activity triggered through the formyl peptide receptor

Inflammation

Signal transduction of hyaluronic acid-peptide conjugate for formyl peptide receptor like 1 receptor

Bioconjug. Chem.

A novel peptide agonist of formyl-peptide receptor-like 1 (ALX) displays anti-inflammatory and cardioprotective effects

J. Pharmacol. Exp. Ther.

LL-37 inhibits serum amyloid A-induced IL-8 production in human neutrophils

Exp. Mol. Med.

An engineered monomer of CCL2 has anti-inflammatory properties emphasizing the importance of oligomerization for chemokine activity in vivo

J. Leukoc. Biol.

n-Nonanoyl-CCL14 (NNY-CCL14), a novel inhibitor of allergic airway inflammation is a partial agonist of human CCR2

Allergy

Review
Peptide drugs to target G protein-coupled receptors