This minireview touches upon the challenges and opportunities peptides experience on the track to become an approved pharmaceutical. Peptide attributes originally considered troublesome with respect to drug development may now turn out to be more convenient rather than unfavourable. Besides characteristic high target affinity, biological peptides often exhibit higher than expected stability. Clearly natural selective pressure has optimised these biomolecules beyond what can be anticipated solely on the basis of their chemical nature. This concept is gradually finding its way into the pharma and biotech industry, as illustrated by a rise in medicinal peptide patent applications and developmental work.

https://repository.tudelft.nl/islandora/object/uuid%3A4e87fb7b-54fd-4386-b9e1-ca1fd16f9be6/datastream/OBJ/download

The emergence of peptides in the pharmaceutical business: From exploration to exploitation

Glucagon-like peptide-1(7-36)amide (GLP-1) is a secreted peptide that acts as a key determinant of blood glucose homeostasis by virtue of its abilities to slow gastric emptying, to enhance pancreatic insulin secretion, and to suppress pancreatic glucagon secretion. GLP-1 is secreted from L cells of the gastrointestinal mucosa in response to a meal, and the blood glucose-lowering action of GLP-1 is terminated due to its enzymatic degradation by dipeptidyl-peptidase-IV (DPP-IV). Released GLP-1 activates enteric and autonomic reflexes while also circulating as an incretin hormone to control endocrine pancreas function. The GLP-1 receptor (GLP-1R) is a G protein-coupled receptor that is activated directly or indirectly by blood glucose-lowering agents currently in use for the treatment of type 2 diabetes mellitus (T2DM). These therapeutic agents include GLP-1R agonists (exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, and langlenatide) and DPP-IV inhibitors (sitagliptin, vildagliptin, saxagliptin, linagliptin, and alogliptin). Investigational agents for use in the treatment of T2DM include GPR119 and GPR40 receptor agonists that stimulate the release of GLP-1 from L cells. Summarized here is the role of GLP-1 to control blood glucose homeostasis, with special emphasis on the advantages and limitations of GLP-1-based therapeutics.

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Regulation of Glucose Homeostasis by GLP-1

For more than half a century, cytotoxic agents have been investigated as a possible treatment for cancer. Research on animal venoms has revealed their high toxicity on tissues and cell cultures, both normal and tumoral. Snake venoms show the highest cytotoxic potential, since ophidian accidents cause a large amount of tissue damage, suggesting a promising utilization of these venoms or their components as antitumoral agents. Over the last few years, we have studied the effects of snake venoms and their isolated enzymes on tumor cell cultures. Some in vivo assays showed antineoplastic activity against induced tumors in mice. In human beings, both the crude venom and isolated enzymes revealed antitumor activities in preliminary assays, with measurable clinical responses in the advanced treatment phase. These enzymes include metalloproteases (MP), disintegrins, L-amino acid oxidases (LAAOs), C-type lectins, and phospholipases A2 (PLA2s). Their mechanisms of action include direct toxic action (PLA2s), free radical generation (LAAOs), apoptosis induction (PLA2s, MP, and LAAOs), and antiangiogenesis (disintegrins and lectins). Higher cytotoxic and cytostatic activities upon tumor cells than normal cells suggest the possibility for clinical applications. Further studies should be conducted to ensure the efficacy and safety of different snake venom compounds for cancer drug development.

/pdf/antitumoral-activity-of-snake-venom-proteins-new-trends-in-u2fpsym21y.pdf

Antitumoral activity of snake venom proteins: New trends in cancer therapy

Oral delivery of therapeutic protein/peptide for diabetes--future perspectives.

Glucagon like peptide (GLP-1) increases insulin secretion but is rapidly degraded (half-life: 2 min in circulation). GLP-1 analog, Exenatide (Byetta) has a longer half life (3.3–4 hrs) with potent insulinotropic effects but requires cold storage, daily abdominal injections with short shelf life. Because diabetic patients take >60,000 injections in their life time, alternative delivery methods are highly desired. Exenatide is ideal for oral delivery because insulinotropism is glucose dependent, with reduced risk of hypoglycemia even at higher doses. Therefore, exendin-4 (EX4) was expressed as a cholera toxin B subunit (CTB)-fusion protein in tobacco chloroplasts to facilitate bioencapsulation within plant cells and transmucosal delivery in the gut via GM1 receptors present in the intestinal epithelium. The transgene integration was confirmed by PCR and Southern blot analysis. Expression level of CTB-EX4 reached up to 14.3% of total leaf protein (TLP). Lyophilization of leaf material increased therapeutic protein concentration by 12–24 fold, extended their shelf life up to 15 months when stored at room temperature and eliminated microbes present in fresh leaves. The pentameric structure, disulfide bonds and functionality of CTB-EX4 were well preserved in lyophilized materials. Chloroplast derived CTB-EX4 showed increased insulin secretion similar to the commercial EX4 in beta-TC6, a mouse pancreatic cell line. Even when 5,000-fold excess dose of CTB-EX4 was orally delivered, it stimulated insulin secretion similar to the intraperitoneal injection of commercial EX4 but didn’t cause hypoglycemia in mice. Oral delivery of the bioencapsulated EX4 should eliminate injections, increase patient compliance/convenience and significantly lower their cost.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/pbi.12008

Oral delivery of bioencapsulated exendin-4 expressed in chloroplasts lowers blood glucose level in mice and stimulates insulin secretion in beta-TC6 cells

Exenatide is the first drug in the incretin mimetic class and is indicated for treatment of type 2 diabetes mellitus. Although structurally similar to the native glucagon-like peptide, this synthetic form has a much longer duration of action. Randomized trials have shown exenatide to be efficacious in improving glycemic control when combined with either metformin or a sulfonylurea. The dose is initially 5 mcg subcutaneously twice daily and may be titrated to 10 mcg subcutaneously twice daily to achieve better diabetes management. Nausea, vomiting, and diarrhea were the most common adverse events reported with exenatide therapy. Exenatide is not associated with hypoglycemia, which may provide advantages over adding insulin to a sulfonylurea or metformin.

Aaron Bond

Papers

Exenatide (Byetta) as a novel treatment option for type 2 diabetes mellitus.