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PEPTIDE TRENDS DECEMBER 2016

MEET US AT COSMETECH IN TOKYO

Cosmo Tech 2017

CosmeTech is Asia's leading exhibition for cosmetic ingredients, contract manufacturing and packaging.

The 2017 edition will take place on January 23rd – 25th at Tokyo Big Sight, Japan. Together with CosmeTokyo, a concurrent show specialized in finished cosmetic products; CosmeTech is Japan's largest comprehensive cosmetics event, covering the entire industry from ingredients, contract manufacturing, and packaging to finished products.

 

The increased interest on peptides as ingredients in cosmetic products, most notably in anti-aging therapy, and last but not least, our offerings for the cosmetic industry, CosmeTech 2017 will be a great opportunity to meet industry partners.

 

We are excited to meet with our customers and discuss how Bachem can help with their cosmetic peptide needs. With our offer for cosmeceutical-related products, our excellent service for custom peptide synthesis and our capabilities for small to industrial scale synthesis of peptides of any complexity we are confident to be the ideal partner in the development and production of cosmetic peptides.

 

We invite you to visit us at our Booth 12-17: please contact us to schedule a meeting in advance.

We look forward to meeting you at CosmeTech 2017!

TOXIC PEPTIDES

Toxins Acting On Ion Channels

Toxic peptides can be used to selectively block ion channels with the aim to study them or to distinguish their functions from other, not channel-dependent physiological processes. The specific and tight binding of toxins moreover can be utilized for the labeling of ion channels in fluorescence microscopy. For this purpose, either biotin-conjugated toxins, labeled with fluorophore-conjugated streptavidin or fluorophore-toxin conjugates can be used [1] (Figure). 

Examples of ion channels investigated using toxins are voltage-gated Ca2+ channels, voltage-gated or Ca2+-activated K+ channels, Na+ channels as well as a variety of receptors, which at the same time function as, or are linked to, ion channels. Toxins acting on voltage-gated Ca2+ (Cav) and voltage-gated K+ (Kv) channels will be discussed in more detail in the following.

Cav channels modulate the efflux of calcium in response to membrane depolarization, and are integral to the membranes of excitable cells. Physiologically, the influx of Ca2+ through membranes has a twofold function, since the Ca2+ ions do not only alter the membrane potential, but also trigger a variety of Ca2+ dependent processes. Accordingly, Cav channels are attributed to several disease patterns, for example to the neurological disorders epilepsy, migraine, and chronic pain [2].

The toxin-specificity of Cav channels depends on the subtype. While Cav2.1 channels can be efficiently blocked with ω-agatoxin IVa, isolated from American funnel web spider venom, Ca2+ flow through Cav2.2 channels can be selectively inhibited using ω-conotoxins GVIA, MVIIA and MVIIC, isolated from the venoms of marine fish-hunting cone snails [1, 2].

Cone snails in general are very interesting species in respect to pharmacologically potent toxins: Each species of cone snails produces more than 1000 conopeptides. So far, only about 0.1 % of them have been pharmacologically characterized, yet many of them with identified clinical potential [3].

Kv channels are the largest group of K+ channels in humans. In excitable cells, opening of Kv channels serves a repolarization or even hyperpolarization of the membrane. Activation of Kv channels reduces, whereas blocking increases the excitability of the cells. In both excitable and non-excitable cells, Kv channels fulfill important functions such as Ca2+-mediated signaling, volume regulation, secretion and proliferation [4]. 

Toxic peptides from diverging species exert their blocking effect on Kv channels in different modes: Toxins from scorpions, sea anemones, snakes and cone snails in most cases bind to the outside of the channel and insert a lysine side chain into it, which occludes the channel like a cork in a bottle. In contrast, spider toxins like hanatoxin interact with the voltage sensor domains and stabilize the closed state of the channels [4].

The channel Kv1.3 is an example of how toxins like margatoxin (scorpion) or Stichodactyla neurotoxin (sea anemone) can modulate Ca2+-dependent cell signaling: Blocking of Kv1.3 channels leads to a depolarization of the T-cell membranes, thus decreasing the driving force for Ca2+ influx through other channels. Since T-cells are not able to compensate the reduced Ca2+ influx, after a cascade of events, this ultimately leads to reduced cytokine secretion and T-cell proliferation [4, 5].

A study using toxin-mediated specific channel labeling is shown below (Figure): An adult frog neuromuscular junction had been stained with biotinylated ω-conotoxin (Bachem product H-6132) and then visualized by exposure to streptavidin Alexa Fluor 488® (green). This toxin localizes the presynaptic N-type calcium channels within active zones of this neuromuscular synapse. In red, an Alexa Fluor 594® conjugated α-bungarotoxin is used as a counter stain for postsynaptic acetylcholine receptors. This toxin staining demonstrates that presynaptic calcium channels and postsynaptic acetylcholine receptors are aligned in their positioning within the synapse.

 

 

Figure 1: Adult frog neuromuscular junction stained using toxins. Courtesy Professor Stephen D. Meriney, PhD, Department of Neuroscience, University of Pittsburgh, PA (USA).

 

Toxins Acting On Receptors

A number of toxins are used to investigate the functions of receptors. Thereby, many toxins act on G-protein coupled receptors (GPCRs), which fulfill about 80 % of the signal transduction across cellular membranes and are drug targets of remarkably high relevance [6].

Mammalian endothelins, the endogenous activators for a family of GPCRs, are highly potent vasoconstrictors. In addition, the endothelin system plays an important role in pain, hypertension, atherosclerosis, cancer and inflammation. Sarafotoxins, discovered in the venom of burrowing asps of the genus Atractaspis, have high structural similarity with mammalian endothelins and function as efficient and selective agonists for endothelin receptors [7].

Other examples for toxic peptides acting on GPCRs are exendin-4 or exenatide, an FDA-approved synthetic drug derived from it. Exendin-4 was isolated from the venom of the lizard Heloderma suspectum. Exendin-4 and exenatide activate glucagon-like peptide-1 (GLP-1) receptors and thus stimulate insulin secretion, slow gastric emptying, and inhibit the production of glucose by the liver. Since exendin-4 (exenatide) is resistant to degradation by the enzyme dipeptidyl peptidase 4, it is of high therapeutic value in the treatment of diabetes [8].

Like the ion channel blocking conotoxins, conopressins were found in the venom of fish-hunting cone snails. Conopressins show structural and functional similarity to the peptide hormone vasopressin, which physiologically activates three subtypes of GPCRs. Conopressins could be beneficial for the development of vasopressin or oxytocin receptor antagonists with tailored selectivity [3].

 

Lipid Bilayer Interacting and Mast Cell Degranulating Toxins

A number of bee and wasp toxins have effects, which are of substantial scientific interest. Melittin for example is a surface-active, highly cytolytic peptide, making up about 50 % of the peptide fraction in the venom of the European honey bee Apis mellifera. Melittin is extensively used for monitoring mechanisms of pore formation and lipid–protein interactions in membranes. Melittin also induces histamine release, presumably by lysis of mast cells, and potentially has anti-viral activity [9, 10].

Mast cell degranulating peptide (MCD or MCDP), also found in European honey bee venom, has antagonistic immunological properties: It is a powerful anti-inflammatory agent, but also induces mast cell degranulation and hence inflammation. In addition, MCD has been shown to function as a neurotoxin with the ability to block a certain class of Kv channels, and to have a cardiovascular effect with the potential to significantly lower blood pressure [10]. 

Mastoparans, isolated from the venoms of several wasp species, can increase the lipid bilayer permeability for hydrophilic molecules and can form pore-like lesions in lipid membranes [11]. They furthermore promote secretion from mast cells by interacting with intracellular, trimeric G-proteins, thus mimicking the action of activated GPCRs [11, 12]. Other effects conferred by wasp toxins include vascular smooth muscle contraction (mastoparan-7) [13] as well as potential anti-tumor properties (mastoparan-7 and polybia) [13, 14].

 

Actin Filament Binding Toxins

Actin filaments are involved in intracellular transport, secretion, cellular motility and cancer transformation in eukaryotic cells. Phalloidin, a bicyclic poisonous heptapeptide of the mushroom Amanita phalloides, tightly binds to F-actin. This is beneficial for the visualization of actin in light microscopy: Binding of phalloidin stabilizes actin filaments against harsh experimental treatment, which facilitates sample preparation. In addition, actin filaments can be stained very specifically with fluorophore-conjugated phalloidins [15].

 

Conclusions

Manifold applications employing toxic peptides in biomedical research exist, rendered possible by the intriguing diversity of toxins in nature. Toxins are used for example to selectively block channels, to activate receptors, to specifically label biomolecules and to study peptide-membrane interactions. Furthermore, toxic peptides can serve as blue prints for drug development.

For experimental work, a broad offering of catalog peptides including numerous natural, conjugated, or modified toxic peptides can be purchased from stock or are commercially available as custom peptides. This significantly improves the availability of the toxins for bench scientists and is of great value for obtaining meaningful and reproducible results in shorter time.

 

Explore our broad offering of catalog toxic peptides, our custom peptide synthesis service as well as further technical information

Toxic Peptides

Custom Synthesis Service

Flyer Toxins

Technical Library

 

 

References

[1]           J. A. Haack et al. Biotinylated derivatives of omega-conotoxins GVIA and MVIID: probes for neuronal calcium channels. Neuropharmacology 32, 1151 (1993)

[2]           B. A. Simms and G. W. Zamponi. Neuronal voltage-gated calcium channels: structure, function, and dysfunction. Neuron 82, 24-45 (2014)
[3]           R. J. Lewis et al. Conus venom peptide pharmacology. Pharmacological Reviews 64, 259-298 (2012)

[4]           H. Wulff et al. Voltage-gated potassium channels as therapeutic targets. Nature Reviews Drug Discovery 8, 982-1001 (2009)

[5]           K. G. Chandy et al. K+ channels as targets for specific immunomodulation. Trends in Pharmacological Sciences 25, 280 (2004)

[6]           R. P. Millar and C. L. Newton. The year in G protein-coupled receptor research. Molecular Endocrinology 24, 261-274 (2010)

[7]           F. Ducancel. Endothelin-like peptides. Cellular and Molecular Life Sciences 62, 2828-2839 (2005)

[8]           B.D. Green and P.R. Flatt. Incretin hormone mimetics and analogues in diabetes therapeutics. Best Practice & Research Clinical Endocrinology & Metabolism. 21, 497-516 (2007)

[9]           H. Raghuraman and A. Chattopadhyay. Melittin: a membrane-active peptide with diverse functions. Bioscience Reports 27, 189-223 (2007)

[10]         M. R. Ziai et al. Mast cell degranulating peptide: a multi-functional neurotoxin. Journal of Pharmacy and Pharmacology 42, 457-461 (1990)

[11]         A. Arbuzova and G. Schwarz. Pore-forming action of mastoparan peptides on liposomes: a quantitative analysis. Biochimica et Biophysica Acta 1420, 139-152 (1999)

[12]         T. Higashijima et al. Mastoparan, a peptide toxin from wasp venom, mimics receptors by activating GTP-binding regulatory proteins (G proteins). Journal of Biological Chemistry 263, 6491-6494 (1988)

[13]         G. Grzesk et al. Direct regulation of vascular smooth muscle contraction by mastoparan-7. Biomedical Reports 2, 34-38 (2014)

[14]         K.R. Wang et al. Antitumor effects, cell selectivity and structure-activity relationship of a novel antimicrobial peptide polybia-MPI. Peptides 29, 963-968 (2008)

[15]         J. Small et al. Visualising the actin cytoskeleton. Microscopy Research and Technique 47, 3-17 (1999)

PEPTIDE TOXINS IN CLINICAL DEVELOPMENT

Peptide toxins found in the venom of a diverse range of animals such as spiders, amphibians, scorpions, insects and marine life are an attractive source of drug candidates due to their high specificity and potency for their molecular targets. The first venom-derived peptide drug, Capoten® (captopril) based on a venom peptide from the deadly Brazilian viper Bothrops jararaca, was approved by the U.S. Food and Drug Administration over thirty years ago for the treatment of hypertension. Additional venom-derived drugs have been approved over the years and the first venom-derived painkiller, Prialt® (ziconotide) based on a venom peptide from the marine cone snail Conus magus, was approved in 2004. Another successful venom-derived peptide is Byetta® (exenatide), a synthetic version of a peptide from the saliva of the Gila monster Heloderma suspectum. Researchers have just started to tap into the potential of peptide venoms as a source of drug leads. It is estimated that there are over 20 million toxins in more than 100,000 venomous animal species that remain to be explored (1).

There are several peptide toxins currently in various clinical phases of development for the treatment of autoimmune disorders, cancer, diabetes and other conditions as shown in Table 1.

 

Table 1: Peptide Toxins in Clinical Development Phase I to Pending Approval (2)

Product Name

Active Ingredient

Condition Treated

Highest Phase

Companies

Mechanism of Action

BLZ100

--

Glioma (I), Skin cancer (I), Soft tissue sarcoma (I), Solid tumors (I)

Phase I

Morphotek Inc, Fred Hutchinson Cancer Research Center, Blaze Bioscience Inc

Diagnostic imaging enhancer

DA3091

exenatide (pegylated)

Non-Insulin-Dependent Diabetes Mellitus(I)

Phase I

Dong-A Socio Holdings

Glucagon-Like Peptide-1 (GLP-1) Receptor Agonist

Exenatide MERCK

exenatide

Non-Insulin-Dependent Diabetes Mellitus(I)

Phase I

Merck & Co Inc

Glucagon-Like Peptide-1 (GLP-1) Receptor Agonist

FT228

exenatide

Non-Insulin-Dependent Diabetes Mellitus(I)

Phase I

Flamel Technologies SA

Glucagon-Like Peptide-1 (GLP-1) Receptor Agonist

NB1001

exenatide

Non-Insulin-Dependent Diabetes Mellitus(I), Short Bowel Syndrome(I), Metabolic Disorders(PC)

Phase I

Amunix Operating Inc, Naia Limited, Diartis Pharmaceuticals Inc, Versartis Inc

Glucagon-Like Peptide-1 (GLP-1) Receptor Agonist

ORMD

0901

exenatide

Non-Insulin-Dependent Diabetes Mellitus(I)

Phase I

Oramed Pharmaceuticals

Glucagon-Like Peptide-1 (GLP-1) Receptor Agonist

PT320

exenatide

Parkinson's Disease(I)

Phase I

Peptron Inc

Glucagon-Like Peptide-1 (GLP-1) Receptor Agonist

Dalazatide

--

Autoimmune Disorders(I), Antineutrophil Cytoplasmic Antibodies Associated Vasculitis(PC), Asthma(PC), Atopic Dermatitis(PC),  Autoimmune Arthritis(PC),  Inflammatory Bowel Disease(PC), Insulin-Dependent Diabetes Mellitus(PC), Lupus Nephritis(PC), Obesity(PC)

Phase I

University of California, Irvine, KPI Therapeutics, Seattle Children's Research Institute, Baylor College of Medicine, University Medical Center Groningen, Debiopharm Group, Kineta Inc, Airmid Incorporated

Cluster of Differentiation 28 (CD28) Receptor Antagonist, Potassium Voltage-Gated Channel, Shaker-Related Subfamily, Member 3 (KCNA3) Blocker

SORC13

--

Solid Tumors(I)

Phase I

Soricimed Biopharma Inc, The University of Texas MD Anderson Cancer Center

Transient Receptor Potential Cation Channel, Subfamily V, Member 6 (TRPV6) Antagonist

AllerB

bee venom phosphor-lipase A2 peptide

Allergy(II)

Phase II

Anergis SA

Not Applicable

Cenderitide

--

Cardiovascular Failure(II)

Phase II

Capricor Therapeutics Inc

Natriuretic Peptide Receptor (NPR) Agonist, Natriuretic Peptide Receptor B (NPR2) Agonist

ITCA650

exenatide

Non-Insulin-Dependent Diabetes Mellitus(PA)

Pending Approval

Intarcia Therapeutics Inc, Les Laboratoires Servier

Glucagon-Like Peptide-1 (GLP-1) Receptor Agonist

 

 

Phase I Candidates

Blaze Bioscience is developing BLZ100, a tumor paint containing chlorotoxin conjugated to indocyanine green dye that circulates within the body and illuminates cancer cells. Chlorotoxin was originally isolated from the venom of the deathstalker scorpion Leiurus quinquestriatus and the peptide possesses cancer targeting properties (2). BLZ100 is being developed as a surgical imaging agent and the tumor paint is currently in Phase I development (3). 

Following the success of Byetta, several companies including Merck & Co, Dong-A Socio Holdings, Naia Limited, Flamel Technologies SA, and Oramed are developing exenatide products for the treatment of type II diabetes. Most of these exenatide products make use of special delivery systems or half-life extension technologies. For example, Flamel Technologies’ exenatide product, FT228, is used in the company’s Medusa® hydrogel depot formulation and Naia Limited’s exenatide product, NB1001, is a conjugate that combines exenatide with XTEN®, a proprietary extended half-life technology (3). 

Dalazatide (formerly ShK186) is being developed by KPI Therapeutics as a treatment for multiple autoimmune diseases. Dalazatide is a synthetic peptide inhibitor of Kv1.3 potassium channels, originally isolated from the sea anemone Stichodactyla helianthus. In 2016, KPI Therapeutics completed a Phase Ib trial of dalazatide in plaque psoriasis (3). In 2017, the company plans to conduct proof of concept trials in myositis and cutaneous lupus (4).

Soricimed Biopharma is developing a peptide derived from the C-terminus of soricidin, a peptide found in the venom of the northern short-tailed shrew. This soricidin fragment, SORC13, acts by inhibiting a non-voltage gated calcium channel found in epithelial cancers. Soricimed Biopharma completed a Phase I study of SORC13 in patients with advanced solid tumor cancers in 2015. Recently, SORC13 was granted orphan drug designation by the U.S. Food and Drug Administration for the treatment of pancreatic cancer and this follows the same designation for ovarian cancer (3).

 

Phase II Candidates

Anergis SA has designed a bee venom vaccine called AllerB that contains Phospholipase A2 peptide. The vaccine is indicated for the treatment of bee venom allergy. AllerB was in Phase I/IIa trials but no development has been reported recently.

Cenderitide is a dual natriuretic peptide agonist that was designed by combining native mammalian c-type natriuretic peptide (CNP) and the C-terminus of the dendroapis natriuretic peptide (DNP) of venom from the green mamba (3). Capriocor Therapeutics is developing Cenderitide for the treatment of heart failure. The product was recently evaluated in two Phase II clinical trials (5).

 

Pending Approval

In November 2016, Intarcia Therapeutics submitted an NDA to the U.S. Food and Drug Administration for ITCA650 in the treatment of type 2 diabetes. ITCA650 provides consistent and continuous subcutaneous delivery of exenatide via an osmotic mini-pump placed under the skin and it is designed to be a twice- yearly therapy. If the product is approved, it will become the first injection-free GLP-1 receptor agonist therapy (3).

 

Conclusion

Peptide toxins represent an interesting treasure trove of unique compounds for potential drug development. To support investigators and organizations exploring peptide toxins, Bachem offers a selection of peptide toxins and modified peptide toxins from stock at shop.bachem.com. In addition, comprehensive custom peptide synthesis services and the production of peptide-based New Chemical Entities are offered.

 

References

(1)   Z. Takacs and S. Nathan. Animal Venoms in Medicine, Encyclopedia of Toxicology (Third Edition). Elsevier (2014)

(2)   L. Dardevet et al. Chlorotoxin: A helpful natural scorpion peptide to diagnose glioma and fight tumor invasion, Toxins (Basel) 7, 1079-1101 (2015)

(3)   Medtrack (2016)

(4)   Dalazatide, KPI Therapeutics (2016)

(5)   Cendertide, Capricor Therapeutics (2016)

 

MEET BACHEM: SUSANNE RODLER, SALES MANAGER CUSTOM SYNTHESIS

Susanne Rodler

PT: What is your official job title at Bachem?

Susanne: Sales Manager Custom Synthesis

 

PT: How long have you been with Bachem? Where did you work before Bachem?
Susanne: I have been working for Bachem since July 2016. Before Bachem I was working as a sales rep for Roche in the area of Munich.

 

PT: Briefly, what do you do at Bachem?

Susanne: I communicate with our customers for custom synthesis peptides and organize the quotation and orders accordingly. The team of custom synthesis also offers advice on sequences and we visit our customers and join conferences. When the projects are starting to be GMP relevant, we transfer the projects to Business Development.

 

PT: What is your academic background/degrees or training?

Susanne: I studied chemistry in Erlangen-Nuremberg, Germany and did my PhD in organic chemistry with focus on dyes.

 

PT: What do you like to do outside of work (interests, hobbies)?

Susanne: Whenever it is possible I like to spend my time in the mountains. During summer time I love to go climbing or do alpine tours and in wintertime I do a lot of skiing, ski tours or simply built a snow man J.

 

PT: What do you like most about your job?

Susanne: R The variety, every day is different and I am working in a close collaboration with our customers.

 

PT: Have you had any particular expectation when you came to Bachem and have these been fulfilled?

Susanne: I hoped for a good working atmosphere and that I have the possibilities to realize my ideas and to get the chance to broaden my knowledge. All expectations have been far exceeded and I am very grateful for my team.

 

PT: Thank you very much Susanne.

PEPTIDE HIGHLIGHTS

LITERATURE CITINGS

Bachem peptides and biochemicals are widely cited in research publications. Congratulations to all our customers with recent publications!

 

Zindel, D., et al.,

Identification of key phosphorylation sites in PTH1R that determine arrestin3 binding and fine-tune receptor signaling.

Biochem. J., 2016. 473(22): p. 4173-4192.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=27623777

 

Wang, X., et al.,

Neutrophil Necroptosis Is Triggered by Ligation of Adhesion Molecules following GM-CSF Priming.

J. Immunol., 2016. 197(10): p. 4090-4100..

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=27815445

 

Hedl, M., D.D. Proctor, and C. Abraham,

JAK2 Disease-Risk Variants Are Gain of Function and JAK Signaling Threshold Determines Innate Receptor-Induced Proinflammatory Cytokine Secretion in Macrophages.

J. Immunol., 2016. 197(9): p. 3695-3704.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=27664279

 

Jaako, K., et al.,

Prolyl endopeptidase is involved in the degradation of neural cell adhesion molecules in vitro.

J. Cell Sci., 2016. 129(20): p. 3792-3802.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=27566163

 

Luczak, S.E., et al.,

The Chlamydia pneumoniae Adhesin Pmp21 Forms Oligomers with Adhesive Properties.

J. Biol. Chem., 2016. 291(43): p. 22806-22818.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=27551038