Peptide Trends January 2021

January 30, 2021

Meet us at Interphex

Bachem Japan KK is participating in the Interphex Week Osaka, Asia’s leading exhibition for the pharmaceutical industry! This year’s edition will be held on February 24 – 26, 2021 as a hybrid event in Osaka, Japan’s largest pharmaceutical cluster.

Interphex Week consists of two exhibitions for pharmaceutical technologies: Interphex Osaka, a B2B trade show specialized in pharmaceutical and cosmetics manufacturing and packagings, and PharmaLab Expo Osaka, which is focused on technologies for Pharma R&D and Drug Discovery.

Bachem‘s pipeline contains more than 150 customer projects in preclinical and clinical phases. In the last couple of years, a number of products in phase III trials received marketing authorization and phase II projects progressed to phase III clinical trials. In addition, Bachem is strategically diversifying its technology platform to include the manufacture of therapeutic oligonucleotides and nucleic-acid-based medicine: a full-service oligonucleotide manufacturing facility is being built at the headquarters in Bubendorf, Switzerland.

The Bachem Japan team is excited to connect with you, learn your needs for peptides and oligonucleotides and discuss how we can meet your API custom manufacturing needs. With our capacity to produce generic peptide API in quantities of hundreds of kilograms and small molecules in tens of tons per year and our record of over 80 DMF filings in the pipeline, we will certainly be able to support the success of your projects from initiation, through all clinical development phases to commercial supply.

We kindly invite you to drop by our Booth 1-7 or to contact us to schedule a meeting in advance. We look forward to meeting you at Interphex Week Osaka 2021!

Fighting drug addiction: Role of cart peptides

Introduction

Cocaine- and amphetamine-regulated transcript (CART) peptides are neuropeptides that are expressed in brain regions associated with reward. The first fragment of CART peptide was discovered by Spiess and coworkers in hypothalamus extracts in 1981 [1]. Then, Douglass and coworkers identified that CART mRNA is expressed within the striatum of psychostimulant-exposed rats [2]. The study has shown that CART mRNA increases with cocaine administration. Cocaine is a strong psychostimulant drug that can easily cross the blood-brain barrier. As effects, it causes the user to feel intense euphoria and it results in increased locomotor activity. Cocaine inhibits the re-uptake of synaptic serotonin, norepinephrine and dopamine, which results in greater extracellular concentrations of these neurotransmitters [3].

Structure of CART Peptides

CART is encoded by the CARTPT gene. Alternative splicing of the CART mRNA results in two transcripts, encoding for a long (102 amino acids) and a short (89 amino acids) precursor (proCART).

The proCART peptides contain several cleavage sites that allow post-translational processing. This processing results in two biologically active CART peptides. CART 55-102 and CART 62-102 are derived from the long proCART peptide, whereas CART 42-89 and CART 49-89 are processed form the short form. Humans only express the short proCART peptide, in rats both the long and short form are produced. In species that express both the long and the short forms of proCART, the amino acid sequences of CART 42–89 and CART 49–89 are identical to those of CART 55–102 and CART 62–102, respectively (Figure 1) [4].

Figure 1: Structure of Cart peptides

Receptors involved with CART Peptides

So far, no specific CART receptor has been identified. However, there is substantial experimental evidence suggesting the existence of several CART receptor subtypes.

For example, several studies have shown that CART peptides could activate three signaling mechanisms, and that they modulate dopamine receptors-related pathways. First, CART 55-102 has been described to inhibit the voltage-gated L-type Ca2+ channels in a pertussis toxin (PTX)-sensitive manner [5]. PTX is an inhibitor of inhibitory-G-protein (Gi/Go)-dependent signaling pathways [6]. Then, CART 55-102 has been described to increase the phosphorylation of cyclic AMP-response-element-binding protein (CREB) in the nucleus of corticotropin-releasing hormone (CRH) neurons located in the hypothalamic paraventricular nucleus in rats [7]. Ultimately, it promotes the expression of the CREB and induces profound antidepressant effects. Numerous genes associated with reward and reinforcement (genes for dynorphin, substance P, and tyrosine hydroxylase, for instance), are regulated via CREB. Therefore, any abnormality in CREB expression may result in anxiogenic and depressive-like disorders. Finally, CART 55-102 has been described to increase extracellular signal-regulated kinase (ERK) phosphorylation in AtT20 and GH3 cells [8]. This effect was blocked by U0126, an inhibitor of MEK, and by PTX.

Besides modulation of dopamine receptors-related pathways, CART peptides have also exhibited elaborated interactions with other neurotransmitter receptors, such as glutamate receptors and γ-aminobutyric acid (GABA) receptors, which further account for attribution of CART peptides to inhibition of psychostimulant-potentiated locomotor activity.

 

Roles of CART Peptides in Drug Abuse

Studies have shown interactions of CART peptides with neurotransmitters, such as dopamine or GABA, involved in the mechanism of action of psychostimulants. CART may alter their activity leading to modulation of psychostimulant associated behaviors. Based on the distribution of CART peptides, they may play a role in several facets of psychostimulant abuse, including the acute reinforcing actions of psychostimulants, the body’s long-term response to psychostimulants such as desensitization to the drug, and drug seeking and impulsivity following drug abuse.

The complex relationship between CART peptides and amphetamine and cocaine remains unclear. To date, studies have shown a clear interaction, but no rational and general mechanism behind. Under certain conditions (increased stress, increased cAMP signaling), CART mRNA and peptide levels are directly affected by cocaine and amphetamine. Furthermore, CART peptides have an effect on (and seem to be affected by) dopamine as well. Ultimately, the regulation of the CART gene and thus, mRNA and peptide levels, appears to involve CREB, a transcription factor which has been associated with cocaine and amphetamine abuse.

Drug addiction is recognized as a psychiatric disorder. This is triggered by a sense of pleasure or gratification in positive reinforcement, and relief of stress and anxiety in negative reinforcement. Cessation of drug use causes depression-like anxiety symptoms, due to decreased functions of neurotransmitters that are associated with acute drug reinforcement effect. All the evidences have shown that CART peptides have roles in reward, reinforcing processes, including the control of feeding, neural development, fear and stress, and sensory processing and they have the functional properties of an endogenous psychostimulant [9]. Drug abuse is a significant problem, in which CART peptides represent a potential treatment of drug addiction.

For organizations and researchers investigating CART peptides, we offer a selection of research peptides at our online shop.

 

References

[1] Spiess, J. et al. Biochemistry, 20, 1982-1988 (1981).

[2] Douglass, J. et al. J. Neurosci. 15, 2471–2481 (1995); Douglass, J. & Daoud, S. Gene, 169, 241–245 (1996).

[3] Pomara, C. et al. Curr. Med. Chem. 19, 5647–5657 (2012).

[4] Rogge, G. et al. Nat. Rev. Neuroscience, 9(10), 747–758 (2008).

[5] Yermolaieva, O. et al. J. Neurosci. 21(19), 7474–7480 (2001).

[6] Mangmool, S. et al. Toxins, 3, 884–899 (2011).

[7] Sarkar, S. et al. Brain Res. 999, 181–192 (2004).

[8] Lakatos, A. et al. Neurosci. Lett. 384, 198–202 (2005).

[9] Kuhar, M. J. et al. Trends Neurosci. 22, 316-320 (1999).

NEW HOPE TO HEAL DRUG ADDICTION AND DEPRESSION

Drug addiction and depression, often going hand-in-hand, have staggering statistics. In 2019, drug use disorders resulted in more than 180 thousand deaths worldwide. According to the World Health Organization (WHO), an estimated 35 million people have a harmful pattern of drug use or drug dependence [1]. Depression affects an even greater number of people with estimates of 264 million people worldwide [2]. Unfortunately, there has been a lack of novel therapies approved for treating depression. To make matters worse, antidepressants often have undesirable side effects such as sexual dysfunction, sedation, weight gain, and movement disorders. Due to high selectivity and low toxicity, peptides are of interest as treatments and researchers expect them to be free of the common side effects of antidepressants. Several peptide drug candidates are in preclinical development for the treatment of drug addiction and/or depression as shown in Table 1.

Drug CandidateCompanyIndication(s)Phase
LCGA-17Lactocore IncAnxiety Disorders, Depression, Post-Traumatic Stress Disorder (PTSD)Preclinical
Peptide for DepressionImpel NeuroPharma IncDepressionPreclinical
PT00114Protagenic Therapeutics IncAnxiety Disorders, Depression, Alcohol Addiction, Drug Addiction, Post-Traumatic Stress Disorder (PTSD), Ischemia, Neurodegenerative Diseases, Spinal Cord Injury, TraumaPreclinical
Synthetic Peptide to Target Kappa Opioid Receptors for Drug AddictionUniversity of KansasDrug AddictionPreclinical

Table 1. Peptides in Development for Treating Drug Addiction and/or Depression

 

Lactocore is developing LCGA-17 as an intranasal delivery treatment for anxiety disorders, depression and post-traumatic stress disorder (PTSD). The peptide drug candidate acts by targeting Gamma-Aminobutyric Acid Type A (GABA-A) receptors [3]. In studies, the candidate demonstrated rapid and long-lasting anti-anxiety and antidepressant activity [4].

Impel NeuroPharma is developing a small peptide, licensed from the Centre for Addiction and Mental Health, for the treatment of depression. This peptide is administered using the company’s Precision Olfactory Delivery® (POD) technology [5]. The peptide disrupts two dopamine receptors, D1 and D2, that bind at higher rates in people with depression. In an animal model of depression, the peptide showed antidepressant effects while total D1 and D2 protein levels remained constant [5].

A peptide licensed from the University of Toronto, PT00114, is under development at Protagenic Therapeutics for several indications including depression, anxiety, mood disorders, opioid addiction and other neurodegenerative disorders including PTSD. PT0014 is a synthetic form of Teneurin C-Terminal Associated Peptide-1 (TCAP-1) that targets Corticotropin-Releasing Hormone (CRH). Studies conducted in rodent models of anxiety and depression have demonstrated that PT00114 has rapid and long-lasting activity [6]. Protagenic Therapeutics plans to submit an IND to the U.S. FDA in the first quarter of 2021 for PT-00114 [6].

Researchers at the University of Kansas are investigating a cyclic tetrapeptide for the treatment, inhibition or prevention of drug and stress-induced cocaine-seeking behavior. The drug candidate acts by targeting the kappa opioid receptors (KOR). In preclinical studies, pretreatment with the peptide prevented both cocaine- and stress-induced reinstatement of cocaine-seeking behavior [7].

 

Conclusion

Research with peptides may lead to new therapies to help millions of people worldwide fighting drug addiction and depression. To support pharmaceutical and biotech companies developing peptide therapeutics, Bachem offers the production of New Chemical Entities and a comprehensive Custom Synthesis Service.

 

References

[1] Drugs (psychoactive). World Health Organization 2021.

[2] Depression. World Health Organization 2021.

[3] GlobalData 2021.

[4] Pipeline. Lactocore 2021.

[5] Novel Small Peptide Antidepressant. Centre for Addiction and Mental Health (CAMH) 2021.

[6] Protagenic Therapeutics Completes $2.0 Million Convertible Note Financing. Protagenic Therapeutics 2020.

Meet Bachem: MARTIN OSTERMAIER

What is your official job title at Bachem?

My job title is Product Manager Research Chemicals and Specialties.

 

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

Before joining Bachem in September 2020, I have worked for Life Sciences startup companies.

 

Briefly, what do you do at Bachem?

I develop, manage and steer Bachem’s Research Chemicals, Catalog Products and Specialties portfolio.

What is your academic background/degrees or training?

I studied biochemistry and did my doctoral research on G protein-coupled receptor (GPCR) signaling. As an ETH Pioneer Fellow, I have learned hands-on how to build startup companies.

 

What do you do for fun?

I enjoy spending time with my family and doing sports with my friends. I am very interested in foreign countries and cultures.

 

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

We are identifying needs of our partners and provide solutions for mutual benefits, by supporting them in their projects technically, scientifically from the development of the API to the commercialization.

What makes a perfect day for you?

It’s a highlight when I see how my work benefits my partners, the customers, and drives business for everyone.

 

What is your business motto?

Think like an entrepreneur to be a successful intrapreneur!

 

What do you like most about your job?

I enjoy the variety of my tasks, the interaction with many professionals from different divisions, and being at the pulse of market development.

 

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

Coming from the startup ecosystem, I expected structured processes and great leverage for new ideas. These expectations have been fulfilled and beyond that, I am happy about the collaborative working environment.

 

What is your preferred peptide?

I have a favor for peptides that bind to GPCRs.

Peptide highlights

V.N.Marty et al.

Long-acting glucagon-like peptide-1 receptor agonists suppress voluntary alcohol intake in male Wistar rats.

Frontiers in Neuroscience 14, (2020)

 

G.Sakamaki et al.

Loss of SUR1 subtype KATP channels alters antinociception and locomotor activity after opioid administration.

bioRxiv 2020.2012.2002.408450 (2020)

 

Z.Tasma et al.

Agonist bias and agonist-dependent antagonism at corticotrophin releasing factor receptors.

Pharmacology Research & Perspectives 8, e00595 (2020)

 

H.E.Yarur et al.

Cross-talk between dopamine D1 and corticotropin releasing factor type 2 receptors leads to occlusion of their ERK1/2 signaling.

Journal of Neurochemistry 155, 264-273 (2020)