UnAcylated Ghrelin (UAG) agonists in the treatment of Type 2 Diabetes and its vascular complications


1- Background: the Ghrelin system

Ghrelin is a 28-amino acid circulating peptide that was initially discovered in 1999 as the endogenous ligand of an orphan receptor, the Growth Hormone (GH) Secretagogue type 1a Receptor (GHS-R1a) (1). Ghrelin is naturally secreted by the stomach, pancreas and a wide variety of cells and tissues, and circulates into two different forms:

  • Acylated Ghrelin (AG), commonly referred to ghrelin, is acylated (octanoyl moiety) on the Serine in position 3,

  • UnAcylated Ghrelin (UAG) is the ghrelin peptide devoid of the acyl moiety.

The acylation of UAG into acylated ghrelin (AG) is catalyzed by Ghrelin O-AcylTransferase (GOAT) and is essential for binding to GHS-R1a (2;3). Thus AG, but not UAG, induces secretion of Growth Hormone (GH) and is responsible for other peripheral and central activities mediated by GHS-R1a (4). AG is an orexigenic hormone that stimulates appetite and induces insulin resistance (1;5). Despite initial interest, the development of AG as a therapeutic drug has been limited by its diabetogenic properties (6-9). Therefore inhibiting AG’s diabetogenic and adipogenic effects is now recognized as a therapeutic target for the treatment of metabolic disorders, such as type 2 diabetes and obesity (10).

2- Pharmacological properties of UAG

Unacylated ghrelin (UAG) is the predominant form of circulating ghrelin (80-90%). UAG, although devoid of GHS-R1a-binding affinity, is an active peptide exerting specific biological activities through a yet undetermined receptor, sometimes supporting, but most often counteracting and opposing the effects of AG (10; 11). Hence, while AG and UAG promote pancreatic ß-cell survival (12;13), UAG has been reported to counteract AG-induced insulin resistance and hyperglycemia (14;15) and to suppress AG-induced glucose output by primary hepatocytes (16). These initial observations are further supported by subsequent pharmacological studies performed in animals and humans which emphasize the antidiabetogenic potential of UAG.

Preclinical data on UAG

In vitro, UAG, in contrast to AG, promotes glucose and FFA uptake by cardiomyocytes, myotubes or adipocytes (17;18). In STZ-induced diabetic rats, UAG administration counteracted STZ-induced hyperglycemia and protected the animals from the STZ-induced decrease in insulin levels, while exerting clear trophic effects on pancreatic islet cell mass (19). In mice on a high-fat diet, UAG administration improved insulin sensitivity and prevented increases in fat mass and body weight without affecting food intake (20). Supporting animal data from literature indicate that over-expression of UAG in transgenic mice promotes glucose tolerance and insulin sensitivity, while reducing fat deposition and triglycerides levels (21;22).

Clinical data on UAG

In T2DM patients, infusion of UAG for up to 16 hours resulted in a reduction of post-prandial hyperglycemia, in line with earlier observations (confidential data on file). In addition, a strong inhibitory effect on blood AG concentrations was observed in these patients (confidential data on file). To date, UAG as bolus injection or short-term infusion has been administered to more than 100 individuals and has been reported to have a safety profile comparable to placebo.

Cardiovascular benefits of UAG

Several published and unpublished reports have shown that UAG exerts beneficial cardiovascular effects (23-25). Very recently, it was e.g. reported that acute administration of UAG, but not AG, restores Endothelial Progenitor Cells (EPC) mobilization in diabetic animals and in T2DM patients, resulting in improved vascular remodeling (26). UAG has also been shown to protect EPCs from oxidative stress and from senescence, two important unwanted processes that are present in diabetic patients. In hindlimb ischemia mouse model, UAG improves functional recovery and muscle regeneration post-ischemia in wild type and ob/ob mice (confidential data on file). Considering the fact that circulating EPCs are biomarkers for vascular functions and cardiovascular outcomes (27;28), these results support the rationale for investigating the effects of UAG analogs on cardiovascular outcome, a highly unmet need in the treatment of the complications of diabetes. In addition, it may pave the way to the development of UAG analogs in macrovascular indications such as peripheral arterial diseases or myocardial infarction.

The UAG development program

Original and promising pharmacological profile

  • [AG] inhibitory effect, insulin sensitizing effect & ß-cell protection
  • Expected positive effects on cardiovascular risk factors

Lead analog ready to enter preclinical development

  • A cyclic 8-AA lead compound, with increased in vitro and in vivo half-life has been selected from a Structure-Activity-Relationship and design program. This analog, derived from a UAG fragment, exhibits the same pharmacological profile as UAG and is expected to enter preclinical development in 2012

Strong IP position

  • Alizé Pharma holds a strong IP position on the AZP-01 program consisting of 4 families with a total of 33 patent applications that are filed internationally and that are related to UAG, its analogs and their potential clinical indications.

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