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PEPTIDE TRENDS MAY 2017

MEET US AT THE APS

The American Peptide Symposium is a biennial event organized by the American Peptide Society, a nonprofit scientific and educational organization dedicated to advancing and promoting knowledge of the chemistry and biology of peptides.

 

This year, the 25th American Peptide Symposium will be held on June 17-22, 2017 in Whistler, BC, Canada.

 

The symposium theme of New Heights in Peptide Research will cover a broad range of topics connecting chemical, materials, biological, pharmaceutical and medical science.

 

The American Peptide Symposium provides a forum to learn and share the latest results with professors, students, postdocs, and industrial researchers who make exciting contributions to peptide research.

 

We invite you to visit us at our Booth #18:please contact us to schedule a meeting in advance.

 

We look forward to meeting you at APS 2017!

DIPEPTIDES AND TRIPEPTIDES

Dipeptides and Tripeptides

Even though they are the smallest peptides, dipeptides and tripeptides can be biologically active or show specific properties. Or, as digestion products of proteins, function as source of amino acids. Two transporter proteins mediate the cellular uptake for further processing of di- and tripeptides. PepT1 located in the brush border membrane of the intestinal epithelium transfers the nutritional peptides from the small intestinal lumen into intestinal absorptive cells (enterocytes). PepT2 expressed in the renal tubules is involved in their re-adsorption from primitive urine.

 

400 different dipeptides can be formed when connecting the 20 proteinogenic amino acids and most of them if not all have been detected in nature. This diversity is increased by involving the side chains of Asp, Glu, or Lys in peptide bond formation, modifications as N-terminal acetylation and C-terminal amidation, and end-to-end cyclization yielding diketopiperazines. Moreover, nonproteinogenic amino acids as Hyp can be incorporated.

 

When synthesizing tripeptides, 8000 different combinations can be obtained from the 20 coded amino acids. Tripeptide hormones such as TRH (Pyr-His-Pro-NH₂, H-4915), MIF-I (H-Pro-Leu-Gly-NH₂, H-4305), or avian bursin (H-Lys-His-Gly-NH₂, H-5920) are further modified as to increase metabolic stability. Unlike dipeptides, tripeptides show a very low propensity for end-to-end cyclization.

 

Antihypertensive di- and tripeptides

Di- and tripeptides are constituents of numerous foodstuffs. A remarkable angiotensin I-converting enzyme (ACE)-inhibiting activity has been determined for a number of short peptides isolated from milk products. The hydrophobic tripeptides IPP and VPP are the best-known examples. Antihypertensive drugs acting by inhibition of ACE as captopril and enalapril mimic Pro-containing tripeptides.

 

Table 1. A choice of antihypertensive di- and tripeptides (for references see the catalog entries).

 

Dipeptide

Prod. Nr.

IC50 (mmol/l)

Tripeptide

Prod. Nr.

IC50 (mmol/l)

H-Ala-Trp-OH

G-1395

6.4

H-Ile-Pro-Pro-OH

H-4632

5

 

H-Ala-Tyr-OH

G-1405

14.2

H-Leu-Pro-Pro-OH

H-6226

9.6

H-Ile-Trp-OH

G-2435

4.7

H-Val-Pro-Pro-OH

H-4634

9

 

H-Ile-Tyr-OH

G-2440

8

H-Ile-Arg-Pro-OH

H-1178

1.8

H-Leu-Trp-OH

G-2605

6.6

H-Leu-Ala-Pro-OH

H-3860

3.5

H-Met-Trp-OH

G-2815

9.8

H-Leu-Arg-Pro-OH

H-1274

0.27

H-Pro-Arg-OH

G-2990

4.1

H-Leu-Gly-Pro-OH

H-3895

0.7

H-Val-Trp-OH

N-1170

0.3

H-Val-Tyr-OH

G-3585

20

 

Di- and tripeptides as taste agents

Short peptides also influence the sensory properties of a foodstuff. Four basic taste categories are recognized by the human tongue: sweet, sour, salty and bitter. Monosodium glutamate represents a fifth one, umami, which enhances or masks flavors.

 

The flavor of a cheese reflects its provenience, age, and other characteristics. Mature cheese often tastes slightly bitter. This sensation is due to short hydrophobic peptides generated from β-casein, diketopiperazines, γ-glutamyl peptides, and others. The bitter taste of a peptide correlates positively with its hydrophobicity. γ-Glutamyl peptides and diketopiperazines have also been detected in foodstuff characterized by a hint of bitterness as roasted coffee. Umami peptides may mask the bitterness of bitter peptides.

 

A further class of taste-modifying peptides, the kokumi peptides, generally enhances the five basic flavors by deepening and rounding them out and improving palatability. In 2014, the kokumi peptide γ-glutamyl-valylglycine was approved as a food additive by the Japanese ministry of health.

 

Table 2. A choice of bitter-, umami-, and kokumi-tasting di- and tripeptides.

 

Bitter Peptides

Prod. Nr.

Umami Peptides

Prod. Nr.

Kokumi Peptides

Prod. Nr.

H-Gly-Phe-OH

G-2175

H-Asp-Ala-OH

G-1550

H-Glu(Gln-OH)-OH

G-1930

 

H-Gly-Leu-OH

M-1460

H-Ala-Glu-OH

G-1200

H-Glu(Leu-OH)-OH

G-1950

Cyclo(-Leu-Trp)

G-4505

H-Asp-Leu-OH

G-1590

H-Glu(Met-OH)-OH

G-3195

 

Cyclo(-Pro-Val)

G-1730

H-Gly-Asp-OH

G-2065

H-Glu(Val-OH)-OH

G-2015

H-Tyr-Tyr-Tyr-OH

H-5230

H-Glu-Glu-Leu-OH

H-1924

Homoglutathione

H-3944

 

(Umami peptides chosen from Y. Zhang et al. 2017)

 

Arg-containing dipeptides as H-Arg-Gly-OH (G-3940) enhance the salty taste of convenience food and could help reducing the salt content.

 

Cosmetic di- and tripeptides

Short peptides are gaining more and more importance as cosmetic ingredients. Their effects vary from skin moisturization to stimulating hair growth.

 

The Bachem Vista site complies with ISO 13485, the high quality standard of the Medical Device and Cosmetic Industry, and is trusted partner to our customers since the certification was achieved. ISO 13485 was chosen for its applicability to many of the site’s customers requiring peptides for use in medical devices and cosmetics, and requiring that supplier quality programs are compliant to their own quality system requirements. The Vista site selected the world renowned and highly respected British Standards Institute (BSI) as the independent organization for certification, and can proudly display the BSI Assurance Mark. Bachem is therefore the ideal partner in the development and production of cosmetic peptides.

 

Table 3. Short cosmetic peptides and their applications. For use in cosmetics, some of the peptides are terminally modified.

 

Peptide

INCI Name

Prod. Nr.

Use

L-Carnosine

Carnosine

G-1250

Anti-oxidant

 

H-Ala-Gln-OH

Alanyl Glutamine

G-1210

Moisturization

Kyotorphin

Dipeptide-1

G-2450

Skin irritation

 

H-Val-Trp-OH

Dipeptide-2

N-1170

Skin conditioning

H-Arg-Ala-OH

Dipeptide-3

G-4170

Moisturization

H-Cys-Gly-OH

Dipeptide-4

G-3755

UV protection

H-Pro-Hyp-OH

Dipeptide-6

G-3025

Anti-aging

H-Lys-Lys-OH

Dipeptide-12

G-2675

Moisturization

Liver Cell Growth Factor (GHK)

Tripeptide-1

H-3510

Anti-aging

Tfa-Val-Tyr-Val-OH

Trifluoroacetyl Tripeptide-2

N-1145

Anti-aging

H-Ala-His-Lys-OH

Tripeptide-3

H-1555

Anti-aging

H-Gly-Pro-Hyp-OH

Tripeptide-29

H-3630

Anti-aging

 

Self-assembling di- and tripeptides

Hydrophobic di- and tripeptides can spontaneously self-assemble to form ordered structures such as nanotubes or hydrogels, which makes then potential tools for areas as biomedical nanotechnology and cell culture. Diphenylalanine, Phe-Phe, is the most prominent example for a nanotube-forming dipeptide. Phe-Phe was identified by truncating the β-amyloid segment KLVFFAE, the motif involved in fibril formation.

 

Table 4. Nanotube-forming dipeptides.

 

Diphenylalanine

H-Phe-Phe-OH

G-2925

H-D-Phe-D-Phe-OH

G-3805

Cyclo(-Phe-Phe)

G-1765

 

Further Peptides

H-Ala-Ile-OH

G-1260

H-Ala-Val-OH

G-1420

H-β-Ala-Phe-OH

G-1335

 

H-β-Ala-Val-OH

G-1430

H-Ile-Ala-OH

G-2370

H-Ile-Val-OH

G-2445

H-Leu-Ile-OH

G-2525

H-Leu-Leu-OH

M-1535

H-Leu-Phe-OH

G-2565

H-Leu-Ser-OH

G-2595

H-Phe-Leu-OH

G-2900

H-Phe-Trp-OH

G-2950

H-Trp-Phe-OH

G-3360

H-Val-Ala-OH

G-3500

H-Val-Ile-OH

G-3540

H-Val-Ser-OH

G-3580

H-Val-Val-OH

G-3595

Cyclo(-D-Trp-Tyr)

G-1805

 

Stable hydrogels for 3D-cell culture can be obtained from Fmoc-Phe-Phe-OH, B-2150.

 

Various bioactive di- and tripeptides

Biological activities of short peptides cover a broad spectrum. A few examples:

 

The dipeptide Ac-Asp-Glu-OH (G-1015) is an important neurotransmitter in the mammalian central nervous system and a source of the excitatory amino acid glutamate. The branched dipeptide H-γ-D-Glu-Gly-OH (G-1945, DGG) is a broad spectrum excitatory amino acid antagonist.

 

The tripeptides diprotin A (H-3825, H-Ile-Pro-Ile-OH) and B (H-5290, H-Val-Pro-Leu-OH) are often-used dipeptidyl peptidase IV (DPP IV) inhibitors. DPP IV is an important target in diabetes research.

 

The tripeptide H-Gly-Pro-Gly-NH₂ (H-9865) inhibits the replication of HIV-1 and improves the antiviral effect of both zidovudine and ritonavir.

 

Explore our broad offering of Di- and Tripeptides and ask for your personal poster.

 

 

References

L. Lemieux and R. E. Simard, Bitter flavour in dairy products. II. A review of bitter peptides from caseins: their formation, isolation and identification, structure masking and inhibition. Lait 1992, 72, 335.

S. Gilead and E. Gazit, Self-organization of short peptide fragments: From amyloid fibrils to nanoscale supramolecular assemblies. Supramolecular Chem. 2005, 17, 87.

J. Wu, R. E. Aluko, S. Nakai, Structural requirements of Angiotensin I-converting enzyme inhibitory peptides: quantitative structure-activity relationship study of di- and tripeptides. J. Agric. Food Chem. 2006, 54, 732.

C. H. Görbitz, Microporous organic materials from hydrophobic dipeptides. Chem. Eur. J. 2007, 13, 1022.

S. Toelstede and T. Hofmann, Kokumi-active glutamyl peptides in cheeses and their biogeneration by Penicillium roquefortii. J. Agric. Food Chem. 2009, 57, 3738.

L. Zhang and T. J. Falla, Cosmeceuticals and peptides. Clin. Dermatol. 2009 27(5): 485.

M. Zhou, A. M. Smith, A. K. Das, N. W. Hodson, R. F. Collins, R. V. Ulijn, J. E. Gough, Self-assembled peptide-based hydrogels as scaffolds for anchorage-dependent cells. Biomaterials 2009, 30, 2523.

K. Ito, A. Hikida, S. Kawai, V. T. Lan, T. Motoyama, S. Kitagawa, Y. Yoshikawa, R. Kato, Y. Kawarasaki, Analysing the substrate multispecificity of a proton-coupled oligopeptide transporter using a dipeptide library. Nat. Commun. 2013, 4, 2502.

J.-H. Wang, Y.-L. Liu, J.-H. Ning, J. Yu, X.-H. Li, F.-X. Wang, Multifunctional peptides have attracted increasing attention in the food science. J. Mol. Struct. 2013, 1040, 164.

P. W. Frederix, G. G. Scott, Y. M. Abul-Haija, D. Kalafatovic, C. G. Pappas, N. Javid, N. T. Hunt, R. V. Ulijn, T. Tuttle, Exploring the sequence space for (tri-)peptide self-assembly to design and discover new hydrogels, Nat. Chem. 2015, 7, 30.

Y. Zhang, C. Venkitasamy, Z. Pan, W. Liu, L. Zhao, Novel Umami Ingredients: Umami Peptides and Their Taste. J. Food Sci. 2017, 82, 16.

DI-AND TRIPEPTIDES IN CLINICAL DEVELOPMENT

The applications for dipeptides and tripeptides are diverse. Some dipeptides such as aspartame have found use as artificial sweeteners in the food industry while other dipeptides are being used as supplements in cell culture media. In the field of cosmetics, tripeptides with skin renewal properties have gained interest as ingredients in anti-aging products (1). In the area of drug development, dipeptides and tripeptides are attractive due to cost-effectiveness, possibility of oral administration, low molecular weight and simplicity for structure-activity studies (2). They are being studied in a variety of therapeutic areas such as oncology, gastroenterology, endocrinology, metabolic and genetic disorders (3). There are several dipeptides and tripeptides that are currently in various phases of clinical development.

 

Some examples of dipeptides and tripeptides in clinical development are shown in Table 1.

 

Table 1: Di- and Tripeptide in Phase I – Pending Approval (3)

 

Product Name

Active Ingredient

Condition Treated

Highest Phase

Companies

A3309

elobixibat

Chronic Idiopathic Constipation(PA), Dyslipidemia(II), Irritable Bowel Syndrome(II)

Pending Approval

AstraZeneca, EA Pharma Co Ltd, Ajinomoto Pharmaceuticals Co Ltd , Mochida Pharmaceutical Co Ltd, Ferring International Center SA, Eisai Inc, Eisai Co Ltd, Ajinomoto Co Inc, Albireo Pharma Inc, Albireo AB

CMS024

tyroserleutide

Hepatocellular Carcinoma(III)

Phase III

China Medical System Holdings Ltd

Evitar

--

Surgical Wound(II)

Phase II

AdeTherapeutics Inc, University of Saskatchewan, Royal DSM NV, DSM Biomedical, Temple Therapeutics BV

 

LH025

--

Inflammatory Bowel Disease(II)

Phase II

Link Health Group

BACPT DP

--

Oncology(I)

Phase I

Duke University, DEKK-TEC Inc

CMS02402

tyroservatide

Non-Small Cell Lung Cancer(I)

Phase I

China Medical System Holdings Ltd

 

Pending Approval

A3309 (elobixibat) is a dipeptide that is being developing by Albireo Pharma for the treatment of chronic idiopathic constipation, dyslipidemia and irritable bowel syndrome. In 2016, Albireo announced positive results from a Phase III clinical trial of elobixibat as a treatment for chronic constipation (4). Albireo Pharma has granted EA Pharma an exclusive license for elobixibat for the treatment of gastrointestinal disorders in Japan and other countries in Asia. EA Pharma has submitted an NDA to the Japanese Pharmaceuticals and Medical Devices Agency (PMDA) for elobixibat for the treatment of chronic idiopathic constipation (3).

 

Phase III Candidates

China Medical System Holdings is developing the tripeptide CMS024 (tyroserleutide) for the treatment of unresectable primary liver carcinoma. CMS024 inhibits the expression of ICAM-1, a cell adhesion factor that is involved in the invasion, adhesion and metastasis of tumor cells. The product is in Phase III clinical trials in China (3).

 

Phase II Candidates

EvitarTM is a dipeptide with anti-fibrotic activity that is being developed by Temple Therapeutics to prevent adhesions following abdominal and pelvic surgeries. Evitar is currently in a Phase II clinical trial for the treatment of post-operative pelvic adhesions (3).

 

LH025 is an anti-inflammatory tripeptide that is being developed by Link Health Group as a treatment of inflammatory bowel disease. The peptide is a Nuclear Factor-Kappa B (NF-kB) inhibitor that works by inhibiting inflammation. The product is currently in Phase II clinical studies (3).

 

Phase I Candidates

China Medical System Holdings is developing a second tripeptide, CMS02402 (tyroservatide), as a treatment for non-small cell lung cancer. CMS02402 is a histone deacetylase (HDAC) inhibitor that acts to induce cell cycle arrest and inhibit the proliferation of tumor cells. In 2006, China Medical Systems Holdings reported that Phase I clinical trials of CMS02402 demonstrated that the peptide is safe and well tolerated by patients. In 2008, the company reported that it received approval from the Chinese State Food and Drug Administration to start a Phase II trial for CMS02402 for the treatment of non-small cell lung cancer (3).

 

DEKK-Tec is developing BACPT DP, a water-soluble dipeptide pro-drug. The product is a topoisomerase I inhibitor. The company has completed Phase I trials of BACPT DP for the treatment of cancer (3).

 

Conclusion

Dipeptides and tripeptides continue to be of interest for therapeutic drug development. Bachem offers over 600 dipeptides and tripeptides for research applications at shop.bachem.com. In addition, we offer a comprehensive custom peptide synthesis service and the production of new chemical entities to assist researchers and organizations studying and developing peptides.

 

References

(1) Tripeptide featured as key ingredient in anti-aging launches, Cosmetics Design (2007)

(2) S. Santos et al., Biomedical applications of dipeptides and tripeptides, Biopolymers. 98, 288-293 (2012)

(3) Medtrack (2016)

(4) Elobixibat, Albiereo (2017)

MEET BACHEM: CAYTIE FRIZZELL, SALES SUPPORT ASSOCIATE

PT: What is your official job title at Bachem?

Caytie: Sales Support Associate

 

PT: How long have you been with Bachem? Where did you work before Bachem?

Caytie: I started working at Bachem in February 2016 so a little over a year. Previously I worked for a small law firm outside of Los Angeles.

 

PT: Briefly, what do you do at Bachem?

Caytie: I assist customers with their orders for catalog products and by addressing any questions or inquiries they may have about Bachem products and services via chat, phone or email.

 

PT: How is the Marketing & Sales team partnering with their customers?

Caytie: We strive to give a personal touch when corresponding with our customers. We want them to understand that they are important and we do so by putting forth our best effort in everything we do.

 

PT: What makes a perfect day for you?

Caytie: The perfect day for me would be on a large body of water, somewhere in the mountains, sipping wine surrounded by good friends.

 

PT: What is your business motto?

Caytie: The greatest assist to any customer service representative is their humanity.

 

PT: What do you like most about your job?

Caytie: The thing I enjoy most about my job would have to be the people. I am lucky to have some pretty great colleagues that are hardworking and kind.

 

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

Caytie: I expected for Bachem to be a friendly and professional organization. My expectations were exceeded when I got here.

 

PT: What is your preferred peptide?

Caytie: Osteocalcin because it is fun to say.

 

PT: Thank you very much Caytie.

LITERATURE CITATIONS

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

 

P.R. Griffiths et al.

Vasopressin V1a receptors mediate the hypertensive effects of [Pyr1]apelin-13 in the rat rostral ventrolateral medulla.

J. Physiol. (2017)

 

A. Schirer et al.

Similarities and differences of copper and zinc cations binding to biologically relevant peptides studied by vibrational spectroscopies.

J. Biol. Inorg. Chem. (2017)

 

N.J. Wewer Albrechtsen et al.

A sandwich ELISA for measurement of the primary glucagon-like peptide-1 metabolite.

Am. J. Physiol. Endocrinol. Metab. ajpendo 00005 02017 (2017)

 

D.J. Polley et al.

Cockroach allergen serine proteinases: Isolation, sequencing and signalling via proteinase-activated receptor-2.

Clin. Exp. Allergy (2017)

 

N. Raj et al.

A fundamental investigation into aspects of the physiology and biochemistry of the stratum corneum in subjects with sensitive skin.

Int. J. Cosmet. Sci. 39, 2-10 (2017)