Proglucagon-Derived Peptides as Therapeutics

Abstract

Initially discovered as an impurity in insulin preparations, our understanding of the hyperglycaemic hormone glucagon has evolved markedly over subsequent decades. With description of the precursor proglucagon, we now appreciate that glucagon was just the first proglucagon-derived peptide (PGDP) to be characterised. Other bioactive members of the PGDP family include glucagon-like peptides -1 and -2 (GLP-1 and GLP-2), oxyntomodulin (OXM), glicentin and glicentin-related pancreatic peptide (GRPP), with these being produced via tissue-specific processing of proglucagon by the prohormone convertase (PC) enzymes, PC1/3 and PC2. PGDP peptides exert unique physiological effects that influence metabolism and energy regulation, which has witnessed several of them exploited in the form of long-acting, enzymatically resistant analogues for treatment of various pathologies. As such, intramuscular glucagon is well established in rescue of hypoglycaemia, while GLP-2 analogues are indicated in the management of short bowel syndrome. Furthermore, since approval of the first GLP-1 mimetic for the management of Type 2 diabetes mellitus (T2DM) in 2005, GLP-1 therapeutics have become a mainstay of T2DM management due to multifaceted and sustainable improvements in glycaemia, appetite control and weight loss. More recently, longer-acting PGDP therapeutics have been developed, while newfound benefits on cardioprotection, bone health, renal and liver function and cognition have been uncovered. In the present article, we discuss the physiology of PGDP peptides and their therapeutic applications, with a focus on successful design of analogues including dual and triple PGDP receptor agonists currently in clinical development.

Therapeutic Peptides Targeting PPI in Clinical Development: Overview, Mechanism of Action and Perspectives

“…This 158-mer small protein is submitted in pancreas, gut and central nervous system to specific posttranslational processing by prohormone convertase enzymes, leading to the generation of shorter fragments (Figure 5). Among them, glicentin-related pancreatic peptide (GRPP), glucagon, intervening peptide-1 (IP-1) and intervening peptide-2(IP-2), major proglucagon fragment (MPGF), oxyntomodulin (OXM), glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2) have a prominent role in glucose control, energy balance and gut homeostasis and were hence proposed as models for drug design (Lafferty et al, 2021).…”

Variation in the Evolution and Sequences of Proglucagon and the Receptors for Proglucagon-Derived Peptides in Mammals

“…The mammalian proglucagon (Gcg) gene encodes three glucagon-like sequences, glucagon, glucagon-like peptide-1 (GLP-2), and glucagon-like peptide-2 (GLP-2), which have diverse hormonal roles in the regulation of metabolism (1)(2)(3)(4). Mammalian Gcg is primarily expressed in the alpha cells of the pancreas, L-cells of the intestine, and some neurons of the nucleus tractus solitarii of the brainstem (1)(2)(3)(4).…”

“…The mammalian proglucagon (Gcg) gene encodes three glucagon-like sequences, glucagon, glucagon-like peptide-1 (GLP-2), and glucagon-like peptide-2 (GLP-2), which have diverse hormonal roles in the regulation of metabolism (1)(2)(3)(4). Mammalian Gcg is primarily expressed in the alpha cells of the pancreas, L-cells of the intestine, and some neurons of the nucleus tractus solitarii of the brainstem (1)(2)(3)(4). Tissue-specific proteolytic processing of the proglucagon (Gcg) precursor protein by prohormone convertase enzymes (5) results in the production of glucagon as the major product secreted from pancreatic alpha cells, while GLP-1 7-37 [which mostly circulates as GLP-1 7-36 amide (4)] and GLP-2 are released from intestinal and neuronal cells (1)(2)(3)(4).…”

“…Mammalian Gcg is primarily expressed in the alpha cells of the pancreas, L-cells of the intestine, and some neurons of the nucleus tractus solitarii of the brainstem (1)(2)(3)(4). Tissue-specific proteolytic processing of the proglucagon (Gcg) precursor protein by prohormone convertase enzymes (5) results in the production of glucagon as the major product secreted from pancreatic alpha cells, while GLP-1 7-37 [which mostly circulates as GLP-1 7-36 amide (4)] and GLP-2 are released from intestinal and neuronal cells (1)(2)(3)(4). The primary function of glucagon is to act as the counter regulatory hormone to insulin with a major role stimulating the production and release of glucose from the liver when blood glucose levels are low (6).…”

“…Miniglucagon, a C-terminal secondary proteolytically processed form of glucagon (Glucagon [19][20][21][22][23][24][25][26][27][28][29], is antagonistic to many of the roles of glucagon (14). Other less studied peptides produced by the proteolytic processing of Gcg, including glicentin-related pancreatic polypeptide (GRPP), major proglucagon fragment (MPGF), and intervening peptide-1 and -2 (IP-1 and IP2), may also have roles in human physiology (1)(2)(3)(4)10).…”