Diabetes mellitus is a metabolic syndrome that is defined by raised plasma glucose levels, accompanied by complete or partial deficiency of insulin. Type II diabetes contributes to more than 90 % of the diabetic cases and it generally manifests itself at older ages or with related diseases (e.g. gastrointestinal tract disorders and obesity). It is a widespread disease that is in continuous rise due to sedentary life styles, excessive food intake and/or genetic predisposal. The International Diabetes Foundation reported that DM would affect more than 300 million people around the world by the year 2025. This number may further increase with the contribution of other metabolic disorders that lead to diabetes. For instance, obese patients often develop Type II diabetes in later stages of their condition. The end result of the disease is often damage to important organs such as eyes, kidney and heart that is caused by the high levels of circulating glucose. Current treatment approaches for the Type-2 diabetes include diet, exercise, and a variety of pharmacological agents including insulin, biguanides, sulfonylureas and thiazolidinediones. These current medications have limited success in controlling blood glucose levels, and have several side effects. An ongoing failure in beta cell function is another aspect of this disease and none of the currently used medications is capable of reversing it.

Recently, discovery of an incretin hormone that can efficiently regulate glucose homeostasis brought about a new therapeutic target in diabetes research. Glucagon-Like-Peptide-1 (GLP-1) is an incretin hormone that is secreted from small intestine in response to glucose levels in plasma. After binding to its cognate receptor (GLP-1R), GLP-1 stimulates release of insulin from pancreatic islets that starts the insulin-signaling cascade and ends up with storage of excess glucose as glycogen. Apart from its glucose lowering properties, GLP-1 also induces satiety after meals and slows down digestion by ceasing gastric emptying which both prevent overeating. This aspect of the peptide makes it even a more potent target as a therapeutic due to possible uses in obesity treatment. GLP-1 itself is also well controlled in the body. First, it is strictly glucose-dependent and therefore secreted when there is an increase in glucose levels. Secretion proceeds in a dose-dependent manner. Second, immediately after GLP-1 reaches circulation, a ubiquitous protease dipeptidyl peptidase IV (DPP-IV) hydrolyses the N-terminus end, rendering it inactive. Although this second feedback mechanism plays an important role in glucose homeostasis in healthy individuals, it constitutes a challenge for using GLP-1 as a therapeutic compound for diabetic patients due to stability problems.

It should be mentioned here that GLP-1 is not the only peptide drug option for diabetes. Amylin is another gastrointestinal peptide that has been identified as a potential therapeutic target. It is secreted after food intake from pancreatic cells, along with insulin. Advanced diabetic patients lack amylin due to loss of β-islets. Although mechanism of action is not well understood, it was shown to suppress glucagon secretion in a glucose-dependent manner and delay gastric emptying. Pramlintide is a synthetic amylin analog that has been approved by the FDA in 2005 for treatment of both Type I and Type II diabetes.

Challenges and drawbacks of peptide drugs

Among many reasons that peptides have been held back from being developed as drugs, low bioavailability is significant. Administration is generally intravenous injection in order to reach the target quickly without getting degraded along the way. Due to numerous proteolytic enzymes in the digestive tract and harsh gastric acid, oral administration is not applicable for peptides. Blood plasma also contains proteases that are responsible for degradation of any immunogenic peptide, therefore shortening the half-life of peptide drugs. Clearance can also be very rapid (mins) via hepatic (liver) and renal (kidneys) routes. Hydrophilicity of a peptide chain can also make it difficult to pass through biological membranes and reach to target organs. Therefore, even for an injectable peptide drug, chemical elaborations of the peptide structure are required to overcome these problems. Compared to protein and antibody drugs, peptides have more potential to be modified and mutated without compromising their activity. Several modifications that are commonly used are amino acid sequence mutations, PEGylation, cyclisation and glycosylation.

In order to enhance the plasma half-life of peptide drugs, chemical alterations such as C-terminal amidation and N-terminal acetylations, and amino acid substitution at protease sensitive sites are often utilized. Most of the time, poor protease stability of α-peptides cannot be improved by using natural L-α-amino acids. In order to maintain a longer plasma life, unnatural amino acids such as D-α-amino acids, side chain modified L-α-amino acids and amino acids with unnatural backbone (β- or γ-amino acids) are used.

Cyclization is another method for increasing proteolytic stability. It can be done via disulfide bond between two cysteine residues or head-to-tail cyclization via amide bond.

Attachment of polyethylene glycol (PEG) increases plasma resistance of the peptides and improves the solubility of larger proteins without affecting their activity. For example, PEGylation of Interferon-α has been shown to extent its serum life. In another case, high molecular weight PEG attachment to trichosantin has yielded low immunogenicty in the new conjugate, due to transfer of non-immunogenic properties of the PEG to the new compound.

Glycosylation is also shown to have dramatic effects on half-life and the immunogenicity of protein drugs. The half-life of the native erythropoietin23 has been improved by extra glycosylations on the protein.


Diren Pamuk, Design and engineering of new glucagonlike-peptide-1 analogues.