MEET US AT IN-PHARMA JAPAN
in-PHARMA JAPAN is an international exhibition specialized in pharmaceutical ingredients. The 2018 edition will take place on June 27-29, 2018 at Tokyo Big Sight, Tokyo, Japan. Co-held with Interphex Japan, the world’s leading event for Pharmaceutical R&D and Manufacturing, in-PHARMA JAPAN 2018 will be the largest ever exhibition, bringing together every key person in the Japanese pharmaceutical market.
Bachem will be present at the in-PHARMA JAPAN, and we would like to meet with you to discuss how we can be a partner for your API custom manufacturing needs. Do not miss the presentation of the Bachem experts: Satoshi Mashiko, Head of Business Development Japan, Bachem AG will present “Bachem. Pioneering Partner for Peptides”, in E-7 (East 4 Hall) on June 27, 2018 at 11:50 AM.
Bachem‘s pipeline contains more than 150 customer projects in preclinical and clinical phases with promising potential: in the last two years, a number of products in phase III trials received marketing authorization and phase II projects progressed to phase III clinical trials. Our services include pegylated peptides, peptides for conjugated NCEs and sterile fill and finish (Clinalfa®).
Another service in our portfolio is the selective chemical glycosylation. The technology is applicable to large scale and has the potential to be applied to a variety of peptides, where we can pioneer the concept of improving current and future drugs. To view our webinar please click here.
We invite you to drop by our Booth #E-42-001 (East Hall 4): please contact us to schedule a meeting in advance.
We look forward to meeting you at in-PHARMA JAPAN 2018!
NPY PEPTIDES
Neuropeptide Y (NPY), peptide YY (PYY) and pancreatic polypeptide (PP) belong to a structurally and functionally related family of peptides (NPY peptides), also known as the neuropeptide Y family. Whereas PYY and PP are gut hormones, NPY is one of the most abundant neuropeptides in the central and peripheral nervous system. All three peptide hormones consist of 36 amino acid residues and are C-terminally amidated.
The functions of the NPY peptides have been implicated in a number of serious disease states. One of the preeminent is obesity. Today, obesity is a concerning health problem in the industrialized countries. According to estimations by the World Health Organization (WHO), about 1.7 billion adults are overweight and 400 million obese, and these numbers are expected to increase. Thereby, also 10 % of the world‘s children‘s under the age of 15 years might be affected by obesity in future.
Obesity itself is a major risk factor for a number of severe diseases and health problems like metabolic disorders, orthopedic problems and cancer. For a long time, obesity had been considered to be a behavioral disorder. Nowadays it is clear that besides environmental conditions the origins of obesity are of physiological and genetic nature.
Due to the physiological functions triggered by the Y receptors, ligands acting on them including the NPY peptides are of greatest interest for the development of drugs against obesity.
In the focus are basically all four Y receptors functionally expressed in humans, which are receptors Y1, Y2, Y4 and Y5: Y1 as a modulator of food intake, Y2, which has potential to induce satiety, Y4 due to its potential role in regulation of food intake and because of its potential to suppress orexigenic and to stimulate anorexigenic signaling pathways as well as Y5, since it is postulated to stimulate food intake.
Particularly interesting in the context of obesity is peptide PYY (3-36), which has been demonstrated to be a specific agonist of Y2 receptors in the arcuate nucleus (ARC). PYY (3-36) has potential to act as an “appetite regulator”, and to serve for a long-term regulation of food intake.
Although a number of peptidic and nonpeptidic Y receptor agonists and antagonistis with potent anti-obesity effects had been developed, they had not yet been converted into clinical tools, referring for instance to a study of Yulyaningsih et al. (2011). Major obstacles remain a lack of selectivity, low oral bioavailability, poor brain penetrability or interaction with other receptors, toxicity or lack of longterm effects. Another problem is posed by the redundancy of the system, which controls feeding. The latter potentially compromises the success in long-term treatments, since the human body is basically capable of circumventing the effect of anti-obesity drugs.
Co-therapies with two or more drugs at once, for example administration of Y5 receptor antagonists in combination with a Y2 receptor agonist, Y1 receptor antagonists or oral anorexiants like sibutramine, have potential to improve the anti-obesity effect. Furthermore, the emerging role of the NPY system for controlling the energy homeostasis besides food intake can provide new opportunities to target the Y receptors. The same applies for the regulation of lipid metabolism by peripheral Y receptors, which could be a target for new medications. Specific roles of the NPY system in aspects of tumor progression and cancer are proposed on basis of the high abundancies of several Y receptors, found in some tumor cell lines. For example, Y1 receptors are overexpressed on breast cancer cells, in primary human sarcomas, cortical adenomas, prostate cancer and ovarian cancer (in concert with Y2 receptors). Remarkable high expression levels of Y2 were additionally identified in human brain tumors, such as neuroblastomas and glioblastomas. Overall, Y receptors belong to the most promising targets for cancer therapy, although they found so far more application in tumor diagnosis, than in therapy.
In cancer treatment, the natural internalization of Y receptors, decorated with ligands carrying diagnostics or potent anti-cancer drugs, presumably will play a central role. Some time ago, the first positive results could be obtained, when breast cancer cells in patients could selectively be labeled via Y1 specific NPY analogs. As another medical application, the suitability of NPY peptides and their receptors as tumor markers in certain tissues is discussed.
The finding that Y receptors, especially Y1, Y2 and Y5, are expressed at high levels in developing and adult hippocampal regions, is an indication that NPY is associated with diseases and repair processes of the CNS. In addition, NPY acts as a neuromodulator and affects the release of several neurotransmitters such as dopamine and glutamate, which bears potential for the treatment of some chronic disorders of the CNS.
However, only limited data so far is available for the role of the NPY system in neurodegenerative conditions like Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and amyotrophic lateral sclerosis. In contrast, a pro-epileptic effect of the activation of Y1 as well as an anti-epileptic effect of the activation of Y2 and Y5 are meanwhile scientifically well established.
Abnormal levels of all NPY peptides have been found with patients and in animal models of human inflammatory bowel disease (IBD), an autoimmune disorder of the digestive tract. The interaction of NPY with immune cells during the inflammatory process could play a main role in IBD. Current treatments of IBD are not completely satisfactory, but NPY antagonists could have potential for ameliorating the inflammation.
Molecular Features
NPY peptides share a high level of homology and up to 92 % conservation in structure between vertebrates and non-vertebrates. NPY itself displays a remarkable degree of sequence conservation: 22 positions out of 36 amino acids are identical in all of the investigated species, and NPY is one of the most evolutionary conserved peptides known. Furthermore, PYY shares 75 % homology with NPY and thus is capable to activate the same receptors (Table 1).
| NERVOUS SYSTEM | RECEPTOR Y1 | RECEPTOR Y2 | RECEPTOR Y4 | RECEPTOR Y5 | |
|---|---|---|---|---|---|
| PREFERRED LIGAND | NPY (Pro34)-NPY Leu31,Pro34)-NPY PYY (Pro34)-PYY (Leu31,Pro34)-PYY | NPY NPY (3-36) PYY PYY (3-36) | PP | NPY NPY (3-36) (Ala31,Aib32)-NPY PYY PYY (3-36) |
|
| EXPRESSION | Central | Cerebral cortex, brainstem and thalamus | Hippocampus, brainstem and hypothalamus | Paraventricular nucleus and hypothalamus | Hippocampus, plexiform cortex of olfactory bulb, suprachiasmatic nucleus and ARC |
| Peripheral | Smooth muscle of blood vessels, immune cells, osteoblasts | Autonomic nerves, gastrointestinal tract, endothelial cells, adipocytes | Colon, small intestine and prostate | ||
| TISSUE WITH HIGHEST EXPRESSION | Smooth muscle of vessels innervated by the sympathetic nervous system | Central and peripheral neurons | Gut | Hypothalamus | |
| PHYSIOLOGICAL FUNCTION | Central | Regulation of food intake, anxiolytic | Inhibition of neurotransmitter release (glutamate). Improved learning and memory | Luteinizing hormone secretion | Stimulation of food intake; anti-epileptic |
| Peripheral | Vasoconstriction, regulation of neurotransmitter release | Inhibition of norepinephrine release (pre-junctional); angiogenesis, adipogenesis (post- junctional) |
In addition to a distinct sequence homology, all members of the NPY family exhibit a hairpin-like three-dimensional structure called pancreatic polypeptide-fold (PP-fold). Data obtained by computer modeling based on the crystal structure of avian PP revealed that this tertiary structure consists of an extended type II polyproline helix (residues 1-8), followed by a type II β-turn and an amphipathic α-helix (residues 15-32). The carboxyterminal residues comprise a flexible turn conformation.
Y Receptors
NPY peptides mediate their biological effects through several Y receptors that belong to the family of G-protein-coupled receptors (GPCRs). GPCRs are characterized by seven transmembrane α-helices that interact with a family of heterotrimeric GTP-binding proteins, referred to as G-proteins. GPCRs are found in a wide range of organisms, and many kinds of chemical messengers act through them.
Five subtypes of Y receptors (Y1, Y2, Y3, Y4, Y5, and y6) could be identified in mammals. In humans, only Y1, Y2, Y4 and Y5 are functionally expressed. The members of the Y receptor family show comparatively low sequence identity and different affinities for their endogenous ligands. All Y receptors are mainly distributed in hypothalamic brain regions, but can also be found in many peripheral tissues, where they mediate diverging effects.
Amino acid Asp6.59 in the extracellular loop three, which is the only fully conserved residue of all so far investigated Y receptors, is crucial for the binding of NPY and PP to all Y receptors. It has been postulated that high affinity interactions with Asp6.59 are established via the conserved residues Arg33 and Arg35 at the carboxy-termini of NPY and PP. The same studies suggest that binding of ligands to the receptors Y1 and Y4 involves different molecular mechanisms, than binding to Y2 and Y5.
Binding of NPY to the Y1-receptor is largely impaired when the N-terminal part of the peptide is removed. Truncations of NPY leading to NPY (2-36), NPY (3-36) or NPY (13-36) result in a marked loss of their affinity and biological activity, which strongly suggests that the Y1-receptor interacts with the N-terminal part of the ligand. Peptides with structural modifications at the C-terminal end, such as (Pro34)-NPY and (Leu31,Pro34)-NPY retain full activity for the Y1-receptor, and lose their affinity for the Y2-receptor. This further indicates that the N-terminal part of the peptide determines its binding to and activity at the Y1-receptor.
The Y4 receptor, also known as PP-preferring receptor, differs substantially from other Y receptors and shares only 30 % primary sequence identity with them. Y4 binds PP with affinities in a picomolar range, while it can only be moderately activated by NPY and PYY. Noteworthy, the relative binding affinities differ between species, and diverging specificities for NPY and PYY for example can be found in rodents. Histochemical studies indicate that Y4 is distributed in the whole body including the brain. It is expressed in the hypothalamus, hippocampus, skeletal muscle, heart, adrenal medulla and cortex, thyroid gland, prostate, small intestine, colon and pancreas. Low expression levels can also be detected in the cerebellum, medulla, and spinal cord of the central nervous system (CNS).
Receptor Y5, also referred to as feeding receptor, is strongly expressed in the hypothalamus, where it stimulates appetite. In the periphery, it seems mainly expressed in the testis. Y5 binds the Y1 agonist (Leu31,Pro34)-NPY, but also has affinity for Y2 agonists such as NPY (2-36), NPY (3-36) and PP. The modified variant (D-Trp32)-NPY appears to act as a partial agonist of Y5. The NPY analog (Ala31,Aib32)-NPY was described as a selective agonist of Y5. This substituted peptide was even more potent than NPY in its capacity to stimulate food intake.
Outlook
Despite of substantial progresses achieved in the understanding of the multiple roles of NPY peptides and their receptors and despite of the advances obtained in respect to some diagnostic applications, therapeutic agents are still lacking. Therefore, existing or new Y receptor ligands are crucially required as tools to explore novel medication strategies. This is where our broad offering of NPY research peptides can substantially contribute to the progress in your research.
Explore our wide selection of Neuropeptide Y (NPY), Analogs and Fragments, Peptide YY (PYY) and Related Peptides and Pancreatic Polypeptides (PP).
References
NEUROPEPTIDE Y FAMILY AND CLINICAL DEVELOPMENT
The NPY family of peptides and the Y receptors through which they act play key physiological roles in regulating food intake, energy homeostasis, anxiety and stress. The NPY family encompasses NPY, PYY and PP. PYY and PP, two gut hormones, signal the brain to lessen food intake, anxiety and depression (1). NPY has many functions and is involved in feeding control and regulating hormones such as luteinizing hormone, adrenocorticotropic hormone, insulin and others. Consequently, the NPY family has attracted interest for the development of treatments for several disorders and diseases. Currently, there are four drug candidates based on the NPY family of peptides in early clinical development as shown in Table 2.)
| Product Name | Condition Treated | Highest Phase | Companies |
|---|---|---|---|
| GT-001 | Obesity | Phase I | Gila Therapeutics Inc |
| Neuropeptide Y | Post-traumatic stress disorder | Phase I | Icahn School of Medicine at Mount Sinai |
| NN-9748 | Type 1 Diabetes; Type 2 Diabetes | Phase I | Novo Nordisk AS |
| NN-9747 | Obesity | Phase I | Novo Nordisk AS |
Phase I Candidates
Gila Therapeutics is developing GT-001, a PYY (3-36) agonist, for the treatment of obesity. This peptide activates NPY-Y2 autoreceptors leading to appetite suppression. The company is developing GT-001 as a lingual formulation for application to the tongue prior to meals (3). In 2017, Gila initiated a Phase I dose escalating study to assess the safety and tolerability of GT-001. The company plans to start a second clinical study of GT-001 in 2018 (2).
Researchers at the Icahn School of Medicine at Mount Sinai are studying NPY as a potential treatment for patients with Post-traumatic Stress Disorder (PTSD). Preclinical studies have shown that NPY can lessen the effects of stress in an animal model of PTSD (4). In 2016, a Phase I dose escalation study of intranasal NPY in PTSD was completed (5).
Novo Nordisk is developing the peptide NN-9748 for the treatment of type 1 and type 2 diabetes. NN-9748 is a NPY receptor Y2 agonist that suppresses appetite. This drug candidate is currently in the Phase I stage of development (2).
In addition, Novo Nordisk is developing NN-9747, a PYY analog, for the treatment of obesity. In 2015, Novo Nordisk initiated a Phase I trial of NN-9747 to investigate safety, tolerability and pharmacokinetics for single and multiple doses of NN-9747. In 2018, the company is planning to commence a Phase Ib study of NN-9747 in combination with semaglutide. Semaglutide (Ozempic®) is Novo Nordisk’s glucagon-like peptide-1 analog that was approved in 2017 for the treatment of adults with type 2 diabetes (2).
Conclusion
NPY receptors are attractive therapeutic targets for obesity and other disorders. To support investigators studying the NPY family, Bachem offers a wide selection of peptides including Neuropeptide Y (NPY), Analogs and Fragments, Peptide YY (PYY) and Related Peptides, and Pancreatic Polypeptides (PP). In addition, Bachem offers a comprehensive custom peptide synthesis service and the production of new chemical entities to assist companies with developing peptide-based therapeutics
References
(1) P. Holzer et al., Neuropeptide Y, peptide YY and pancreatic polypeptide in the gut–brain axis, Neuropeptides. 46(6), 261-274 (2012).
(2) GlobalData (2018)
(3) Product Pipeline, Gila Therapeutics (2017)
(4) L. Serova, et al., Single intranasal neuropeptide Y infusion attenuates development of PTSD-like symptoms to traumatic stress in rats, Neuroscience. 236, 298-312 (2013)
(5) A dose escalation study of intranasal neuropeptide Y in post-traumatic stress disorder (PTSD), ClinicalTrials.gov (2016)
MEET BACHEM: AHMET YEGIT
What is your official job title at Bachem?
Marketing Specialist Business Intelligence.
Briefly, what do you do at Bachem?
I focus on deploying digital business platforms. Through these activities I can push forward customer-centric business processes in-line with our commitment as «Pioneering Partner for Peptides.»
What is your academic background/degrees or training?
I hold a Bachelor degree in business with a major in lifecycle management of medical prescription products and an MBA with a major on pharmaceutical carve-outs.
What do you like to do outside of work?
I love writing. With the birth of my first child, I started writing poems which evolved over time into written poetry slams. My next writing project will be a longer script with the potential to develop to a short novel. Besides, I am currently undertaking training to obtain my sailing license.
What is your business motto?
In business intelligence you have to think ahead. This boils down to identifying trends and strategies in the world of today’s growing data. In order to finding «the needle in the haystack» patience is key and therefore my business motto.
What do you like most about your job?
You grow with your challenges. I had the chance to help shape the state-of-the-art IT environment at Bachem, and move us to the next level of organizational excellence. The opportunity to collaborate with colleagues from around the world to design global solutions is one of a kind.
What is your preferred peptide?
I am intrigued by how proteins have been developed in biologicals and the remaining challenges of oral dosage forms. Thus, the peptide business remains highly dynamic and I am pleased to be a part of this industry.
Thank you very much Ahmet.
Peptide highlights
Interesting news about peptides in basic research and pharmaceutical development:
Double-bridged peptides bind any disease target-Drug Target Review
Experimental drug switches off hunger in patients with genetic obesity-GEN
The xB3 platform efficiently delivers antibodies across the BBB at therapeutic doses-EurekAlert!
Building better beta peptides-EurekAlert!
LITERATURE CITATIONS
Bachem peptides and biochemicals are widely cited in research publications. Congratulations to all our customers with recent publications!
M. Diaz-delCastillo et al.
Neuropeptide Y is up-regulated and induces antinociception in cancer-induced bone pain.
Neuroscience 384, 111-119 (2018)
O. Fatoba et al.
Activation of NPY-Y2 receptors ameliorates disease pathology in the R6/2 mouse and PC12 cell models of Huntington’s disease.
Experimental Neurology 302, 112-128 (2018)
A.P. Marques et al.
Dipeptidyl peptidase IV (DPP-IV) inhibition prevents fibrosis in adipose tissue of obese mice.
Biochimica et Biophysica Acta (BBA) – General Subjects 1862, 403-413 (2018)
L. Medzikovic et al.
Nur77 protects against adverse cardiac remodelling by limiting Neuropeptide Y signalling in the sympathoadrenal-cardiac axis.
Cardiovascular Research (2018)
B. Oztas et al.
The effect of leptin, ghrelin, and neuropeptide-Y on serum Tnf-Alpha, Il-1beta, Il-6, Fgf-2, galanin levels and oxidative stress in an experimental generalized convulsive seizure model.