Exendin‐4 from Heloderma suspectum venom: From discovery to its latest application as type II diabetes combatant

Abstract

Type II diabetes mellitus (T2DM) is a chronic non-communicable disease due to abnormal insulin actions causing uncontrolled hyperglycaemia. The treatment for T2DM, for instance, metformin and incretin mimetic, mainly focuses on the restoration of insulin sensitivity and secretion. Exendin-4 is a short incretinmimetic peptide consisting of 39 amino acids. It is discovered in the venom of Heloderma suspectum as a full agonist for the glucagon-like peptide 1 (GLP-1) receptor and produces insulinotropic effects. It is more resistant to enzymatic degradation by dipeptidyl-peptidase-4 and has a longer half-life than the endogenous GLP-1; thus, it is further developed as an incretin hormone analogue used to treat T2DM. The helical region of the peptide first interacts with the extracellular N-terminal domain (NTD) of GLP-1 receptor while the C-terminal extension containing the tryptophan cage further enhances its binding affinity. After binding to the NTD of the receptor, it may cause the receptor to switch from its auto-inhibited state of the receptor to its auto-activated state. Exendin-4 enhances the physiological functions of β-cells and the up-regulation of GLP-1 receptors, thus reducing the plasma glucose levels. Moreover, exendin-4 has also been found to ameliorate neuropathy, nephropathy and ventricular remodelling. The therapeutic effects of exendin-4 have also been extrapolated into several clinical trials. Although exendin-4 has a reasonable subcutaneous bioavailability, its half-life is rather short. Therefore, several modifications have been undertaken to improve its pharmacokinetics and insulinotropic potency. This review focuses on the pharmacology of exendin-4 and the structure-function relationships of exendin-4 with GLP-1 receptor. The review also highlights some challenges and future directions in the improvement of exendin-4 as an anti-diabetic drug.

An Economic Dilemma between Molecular Weapon Systems May Explain an Arachno-Atypical Venom in Wasp Spiders (Argiope bruennichi)

“…ITP/CHH peptides have also been recruited into the venom systems of ticks and wasps and are not restricted to the HAND family. For example, emerald jewel wasp (Ampulex compressa) venom contains tachykinin and corazonin neuropeptides that induce hypokinesia in cockroaches [86], whereas exendin from the venom of helodermatid lizards is a modified glucagon-like peptide that interferes with pancreatic insulin release [87]. Amphibians have also recruited a variety of hormone peptides as skin toxins [88][89][90][91].…”

An economic dilemma between weapon systems may explain an arachno-atypical venom in wasp spiders (Argiope bruennichi)

“…ITP/CHH peptides have also been recruited into the venom systems of ticks and wasps and are not restricted to the HAND family. For example, emerald jewel wasp (Ampulex compressa) venom contains tachykinin and corazonin neuropeptides that induce hypokinesia in cockroaches (Arvidson et al, 2019), whereas exendin from the venom of helodermatid lizards is a modified glucagon-like peptide that interferes with pancreatic insulin release (Yap and Misuan, 2019). Amphibians have also recruited a variety of hormone peptides as skin toxins (Gaudino et al, 1985;Roelants et al, 2010;Roelants et al, 2013;Lüddecke et al, 2018).…”

Potential Therapeutic Applications of Synthetic Conotoxin s-cal14.2b, Derived from Californiconus californicus, for Treating Type 2 Diabetes

“…The development of novel combinations in treatment for T2DM (for instance, metformin and incretin mimetic) focuses on the restoration of insulin sensitivity and secretion. A peptide discovered in Heloderma suspectum venom, consisting of 39 aminoacids with insulinotropic activity, called Exendin-4, is a short incretin-mimetic peptide with full agonist for the glucagon-like peptide 1 (GLP-1) receptor and produces insulinotropic effects, recently described with activity in Alzheimer disease stablish a solid precedent for T2DM therapies based on promising peptide compounds extracted from venomous animals [20][21][22][23].…”