WHAT IS BEHIND STRESS?
Introduction
Stresscopin and stresscopin-related peptides (urocortin III and urocortin II respectively) are part of the corticotropin-releasing factor (CRF) family, which also includes CRF and urocortin. CRF has first been discovered in 1955, but it was in 1981 that Vale et al. succeeded in isolating and describing CRF, as 41 amino acids, from the ovine hypothalamus. Later studies have revealed the presence of highly homologous proteins in other mammalians such as rat and human. Urocortin II (Ucn II) and urocortin III (Ucn III) have been identified in rat, human and mouse.
CRFs are peptide hormones, which play biological roles in generating the stress response by acting at CRF1 and CRF2 receptors. Ucn III was identified by searching in the public human genome databases and revealed to have a significant sequence similarity to Ucn II. The genes encoding these peptides were expressed in diverse peripheral tissues as well as in the central nervous system. Ucn II and Ucn III are expressed in the brain. Additionally, it has been reported that Ucn III is expressed in the peripheral tissues such as gastrointestinal tract, pancreatic islets, and skin.
Structure
To date, three urocortin peptides have been described in mammals: urocortin (Ucn), Ucn II and Ucn III. Urocotins, just like many hormones, are derived from a precursor protein, designated as prepro-proteins. Ucn II encodes a prepro-protein of 112 amino acids and a mature protein of 41 amino acids whereas Ucn III encodes a prepro-protein of 161 amino acids and a putative mature protein of 38 amino acids.
Ucn II (human)
Ucn III (human)
Corticotropin-releasing factor receptors
The corticotropin-releasing factors act through activation of two receptors: CRF1 and CRF2, each encoded by a separate gene (CRHR1 and CRHR2 respectively). Primary functional CRF1 receptor is a peptide composed of 415 amino acids, arranged in seven hydrophobic alpha-helices. CRF1 and CRF2 receptors are 70% homologous, the greatest divergence between the two lies at the N-terminus of the protein. CRF receptors are G-protein-coupled receptors (GPCRs) of the secretin receptor family. They are important mediators in the stress response. CRF1 receptor mediates ACTH (adrenocorticotropic hormone) responses to stress, whereas CRF2 receptor mediates stress-coping responses including anxiolysis, anorexia, vasodilatation, a positive inotropic action on myocardium, and dearousal. CRF and Ucn I bind to both CRF1 receptor and CRF2 receptor, whereas Ucn II and Ucn III are specific ligands for CRF2 receptor.
Roles of stresscopin and stresscopin-related peptide
Abnormal signaling at corticotropin-releasing factor CRF1 and CRF2 receptors might contribute to the pathophysiology of stress-related disorders such as anxiety, depression and eating disorders in addition to cardiac and inflammatory disorders. The four mammalian CRF-related peptide hormones, (CRF, Ucn, Ucn II and Ucn III) show different specificity to CRF1 and CRF2 receptors and the optimal responses to stress depend on an integrated release of these endocrine and paracrine ligands in a tissue specific and time-coordinated manner. The main function of CRF and Ucn is the stimulation of the pituitary synthesis of ACTH, as part of the hypothalamus–pituitary–adrenal (HPA) axis, the two components of the fight-or-flight response to stress. ACTH finally stimulates glucocorticoid secretion by the adrenal cortex. The preclinical and clinical development of specific small-molecule antagonists of the CRF1 receptor opens new avenues for the treatment of psychiatric and neurological disorders. CRF1 receptor antagonists are being actively studied as possible treatments for depression and anxiety.
On the other hand, as mentioned previously, Ucn II and Ucn III do not stimulate ACTH secretion, as they only bind to the CRF2 receptor. They are involved in initial stress-induced responses, such as gluconeogenesis and increases in arterial pressure and heart rate, which provide a vital short-term metabolic lift. However, prolonged or inappropriate exposure to stress can compromise homeostasis thereby leading to disease. It has been described that treatment with Ucn II or Ucn III suppressed food intake, delayed gastric emptying and decreased heat-induced edema. Thus Ucn II and Ucn III might represent endogenous ligands for maintaining homeostasis after stress, and could allow the design of drugs to ameliorate stress-related diseases. Additionally they have been shown to exert anxiogenic effect.
References
Saffran, M. et al. Stimulation of the release of corticotropin from the adenohypophysis by a neurohypophysial factor, Endocrinology, 57(4), 439–444 (1955).
Buckinx et al. Gastrointestinal expression of CRF-related peptides, Front. Neurosci. 5(54), 1-14 (2011)
Lewis K, et al. Identification of urocortin III, an additional member of the corticotropin-releasing factor (CRF) family with high affinity for the CRF2 receptor. Proc Natl Acad Sci USA 98, 7570–7575 (2001)
Reyes TM, et al. Urocortin II: a member of the corticotropin-releasing factor (CRF) neuropeptide family that is selectively bound by type 2 CRF receptors. Proc Natl Acad Sci USA 98, 2843–2848 (2001)
Pelleymounter, M.A. et al. Behavioral and neuroendocrine effects of the selective CRF2 receptor agonists urocortin II and urocortin III, Peptides, 25 (4), 659–666 (2004)
Nozu, T. Peripheral urocortin delays gastric emptying: role of CRF receptor 2, Am. J. Physiol. 276 (4), G867-G874 (1999)
Hsu, S. Y. Human stresscopin and stresscopin-related peptide are selective ligands for the type 2 corticotropin-releasing hormone receptor, Nature Med. 7(5), 605-611 (2001).
COPING WITH STRESS: PEPTIDE THERAPIES
Stresscopin (Urocortin III) and stresscopin-related peptide (Urocortin II) are part of the corticotropin-releasing factor family. This family of peptides is involved in responses to physiological stress and in the regulation of cardiovascular, gastrointestinal systems and inflammation. By agonizing corticotropin-releasing factor (CRF) type 2 receptor, stresscopin improves cardiac output and heart rate and therefore, the peptide has gathered attention as a potential therapeutic for heart failure patients (1). Currently, Renova Therapeutics has a stresscopin peptide, RT-400, in Phase II of clinical development and a stresscopin-related peptide gene product, RT-200, in preclinical development as shown in Table 1.
| Product Name | Company or Organization | Highest Phase | Indication |
|---|---|---|---|
| RT-400 (stresscopin) | Renova Therapeutics | Ph II | Acute Decompensated Heart Failure |
| RT-200 (Urocortin II Gene Therapy) | Renova Therapeutics | Preclinical | Type 2 Diabetes |
Candidates
Renova Therapeutics is developing RT-400 (formerly JNJ-39588146), human stresscopin, for the treatment of Acute Decompensated Heart Failure (ADHF). In 2017, Renova Therapeutics acquired the rights to the investigational new drug (IND) dossier for stresscopin from Janssen Pharmaceuticals. RT-400 is a corticotropin-releasing factor (CRF) type 2 receptor (CRF2) selective agonist and Renova plans to develop it as a peptide infusion product (2).
Renova Therapeutics is also developing RT-200, urocortin II gene therapy, for the treatment of type 2 diabetes. The product candidate consists of urocortin II transgene which is delivered via adeno-associated virus type 8 (AAV8). In preclinical studies, urocortin II gene transfer resulted in increased insulin sensitivity and glucose disposal and provided long-lasting resolution of abnormal glucose homeostasis. In addition, urocortin II gene transfer was shown to reduce fatty infiltration of the liver in two mouse models of insulin resistance (3). RT-200 may also be a potential treatment for other cardiovascular and metabolic diseases such as type 1 diabetes, obesity, non-alcoholic fatty liver disease (NAFLD), metabolic syndrome and congestive heart failure (2).
Conclusion
Stresscopin / urocortin peptides are potential therapeutics for cardiovascular diseases such as heart failure and metabolic diseases such as diabetes. For organizations and researchers investigating stresscopin and urocortin peptides, Bachem offers a selection of research peptides. In addition, Bachem offers a custom peptide synthesis service and the production of New Chemical Entities.
References
1. C.A.Makrewich, et al. Comparative effects of urocortins and stresscopin on cardiac myocyte contractility. Journal of Molecular and Cellular Cardiology 2015, 86, 179-186.
2. GlobalData 2020.
3. RT-200 (Urocortin 2 Gene Transfer). Renova Therapeutics 2020.
MEET BACHEM: SIMON SCHLÄPPI
What is your official job title at Bachem?
I am in the role of the group leader Business Applications at Bachem Global IT.
Briefly, what do you do at Bachem?
As an internal service provider, we advise our business departments on how to support their business processes with information technology, how to understand the dependencies between the various business applications and how to have the technical knowledge to maintain and further develop them together with specialized external partners. Some of the applications are very specific solutions and support dedicated business units. Broader applications for collaboration and workflows serve the whole group. The integration between these information systems is a further focus of our team.
What do you like most about your job?
It is most rewarding to develop and optimize solutions together with our colleagues from other departments and see how we can help them to be even more successful through the use of information technology.
What is your business motto?
Whatever you do, be passionate about it and continuously develop your skills.
What is your academic background/degrees or training?
I started out with vocational training in technical IT and continued with a higher education in applied computer science. Currently I am getting my BSc in Business Information Technology while working 90%.
What do you like to do outside of work?
A lot of my leisure time, I spend with my family. Besides that, I like to read books and do some sports, especially bouldering and running.
Thank you very much Simon.
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LITERATURE CITATIONS
Bachem peptides and biochemicals are widely cited in research publications. Congratulations to all our customers with recent publications!
A.K.Rajbhandari and V.P.Bakshi
Repeated norepinephrine receptor stimulation in the BNST induces sensorimotor gating deficits via corticotropin releasing factor.
Neuropharmacology 172, 108090 (2020)
I.Oliva et al.
Cocaine experience abolishes the motivation suppressing effect of CRF in the ventral midbrain.
Addiction Biology n/a, e12837 (2019)
G.K.Parra-Mercado et al.
CRF1 receptor signaling via the ERK1/2-MAP and Akt kinase cascades: roles of Src, EGF receptor, and PI3-kinase mechanisms.
Frontiers in Endocrinology 10, (2019)
D.Saul et al.
Changes in musculoskeletal system and metabolism in osteoporotic rats treated with urocortin.