The most frequently used peptide/protein drugs can be classified in three main groups. Group I includes exogenously administered protein drugs in case of a deficiency. Insulin for Type I diabetes, growth hormones for treatment of growth factor deficiency in children, Protein C supplements for prevention of venal thrombosis or blood clotting factors in case of haemophilia are few examples. Group II consists of monoclonal-antibody-based drugs for autoimmune diseases such as allergy, arthritis and even for certain cancers. This group actively binds and manipulates a molecule or an organism that is the cause of malfunction or disease. Monoclonal antibodies that target and neutralize the effects of tumor necrosis factor (TNF) have been successful for treatment of rheumatoid arthritis and inflammatory bowel syndrome. Rituximab and cetuximab are important antibody treatments in lymphoma and colorectal cancer respectively. While the former binds to an over-expressed transmembrane protein on cancer cells and facilitates their destruction by the immune system, the latter targets epidermal growth factor of affected cells to impede their growth and proliferation. Group III includes vaccines as a preventative way to overcome infectious diseases. Hepatitis B vaccine significantly protects those who are administered with a non-infectious protein of hepatitis B surface antigen. A approved vaccine against human papillomavirus (HPV) is shown to prevent not only genial warts, but also certain cervical cancers. Another example is the anti-Rhesus D antigen that is a long-used vaccine for desensitization of Rh-negative mothers towards Rh-positive fetus, in order to prevent immune reactions and miscarriages in subsequent pregnancies.
Currently, over 200 biopharmaceuticals that include peptide, protein and antibody-based drugs are in use in clinic. Within these molecules, therapeutic peptides with <50 amino acids make up more than 60 brand-name drugs. Some of these are antidiabetic peptides such as amylin, exentide and liraglutide for treatment of Type I and/or Type II diabetes, angiotensin converting enzyme (ACE) inhibitors for treatment of hypertension, anti-HIV peptides against AIDS infection, calcitonins for treatment of postmenopausal osteoporosis and Paget’s disease, central nervous system (CNS) agents to manage severe chronic pain, gonadotropin releasing hormone derivatives for treatment of advanced forms of prostate cancer and breast cancer, oxytocin for initiation of uterine contractions and prevention of postpartum haemorrhage, somatastatin analogues for treatment of acromegaly and carcinoid tumors and vasopressin analogues for diabetes insipidus. In addition, some peptides are used solely for diagnostic purposes such as, secretins (for pancreatic dysfunction) and adrenocorticotropic hormone derivatives (for detection of adrenocortical insufficiency).
Compared to higher molecular weight biopharmaceuticals (protein and antibody drugs), peptides have more potential to be modified and mutated without compromising their activity. Owing to their small size, penetration at the target site can be obtained when proper modifications are done. Manufacturing small peptides are more affordable than synthesis of larger proteins or production of monoclonal antibodies, and the shelf-life of peptides is generally longer.
Peptide drugs carry even superior advantages over small organic compounds. First, they can target a larger interface on a protein/enzyme that leads to better specificity, efficacy and selectivity. Most peptide drugs are receptor agonists and are derived from natural ligands of the target receptor. Because of the exclusive interactions of the peptide drugs with their target receptors/proteins, they do not display cross-reactivity, thus minimizing the side effect. In addition, they are less likely to elicit an immune response since they are derived from naturally occurring peptides of the body. Moreover, small amounts of the peptides suffice for activation of their receptors, which reduces the dosage of the drug. Although proteolysis is a big problem for small peptides, their degradation by-products are just small peptide fragments or amino acids and are not toxic. Clearance of these molecules is easily done without any damage or accumulation in organs.
Diren Pamuk, Design and engineering of new glucagonlike-peptide-1 analogues
]]>However, several barriers prevent broad application of islet transplantation even within this select patient group. The relatively limited availability of cadaveric pancreata is especially critical, since not every islet isolation attempt currently yields an adequate mass of tissue for transplant. Additionally, more than one islet infusion is often necessary to achieve insulin independence. Genetically modified tissue and alternative sources of insulin secreting tissue (porcine or otherwise) could be longterm solutions to this problem. However, many centers are seeking augmentative therapy to islet transplantation. The ideal candidate would both reduce the amount of islet tissue needed to render and maintain the patient insulin independent and be appropriate for concurrent use with immunosuppressive therapy.
Recent reports, including from a multi-center trial of the Edmonton Protocol, show that graft function declines markedly in transplanted patients with time. This evanescence of islet graft function may be the combined result of allograft rejection, autoimmune diabetes recurrence or islet metabolic burnout. Immunosuppressive agents, although beneficial in preventing islet rejection, may have side effects including diminishing islet function or inducing islet death. Although initial reports suggested that sirolimus, one such immunosuppressive drug, did not have detrimental effect on islet function, several recent investigations have shown that sirolimus has a negative impact on (3-cell function by directly reducing viability, preventing VEGF-mediated angiogenesis, and preventing neogenesis of B-cells from co-transplanted ductal cells.
Glucagon-like peptide 1 (GLP-1) receptor agonists are emerging therapeutic options in the field of type 2 diabetes. GLP-1, an incretin hormone, exerts effects through the specific GLP-1 receptor (GLP-1 R), including stimulation of insulin secretion, suppression of glucagon secretion, slower gastric emptying, and increased satiety. Native GLP-1 administration has limited therapeutic benefit due to its short biological
half-life (several minutes). However, GLP-1 analogues, including exenatide (half-life 60-90 minutes) and liraglutide (half-life 13 hours when administered subcutaneous) are more promising candidates. GLP-1 analogues have recently been discovered to have beneficial effects as adjunct therapy in type 1 diabetes mellitus models, and in pancreatic islet transplant pre-clinical models. Furthermore, some groups have studied these analogues in human islet transplantation which has provided evidence that isolated islets remain responsive to GLP-1 receptor agonists. Liraglutide is an especially attractive candidate for islet transplantation, in addition to its long half-life, it has been reported to maintaining glycemic control in type 2 diabetes with a low risk of hypoglycemia.
However, current literature on the therapeutic role for GLP-1 analogues is limited to observational rather than mechanistic studies in islet transplantation. Furthermore, there is need to understand whether documented functional effects of GLP-1 analogues in islet transplant can circumvent immunosuppressive toxicities on islets, especially those of sirolimus which are of particular concern and have been well described elsewhere.
The article report the investigation of liraglutide in islet transplantation. It investigated both the effect of liraglutide on islet engraftment in the short and long term. Furthermore, it investigated the mechanism of liraglutide action in the setting of islet transplantation. Finally, it sought to investigate the ability of liraglutide to improve islet engraftment in the presence of the immunosuppressive agent sirolimus at clinically relevant blood levels.
Reference:
SHAHEED MERANI. ENGRAFTMENT AND FUNCTION IN PANCREATIC ISLET TRANSPLANTATION
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