Objective
The major goal of this research proposal is to generate a rapid-acting, stable, and potent insulin analog with a short tail of action to improve blood glucose control in people with T1D and be used artificial pancreas systems in the future.
Background Rationale
Predatory marine cone snails use a wealth of compounds in their venoms that potently disrupt the behavior and physiology of their prey, including fish. Because many of the pathways affected in prey also serve vital functions in humans, cone snail toxins have become drugs and drug leads for several human disorders. This includes pain, epilepsy, stroke and heart failure. The majority of cone snail venom components are neurotoxins, compounds that target parts of the prey’s nervous system. Our recent discovery of an insulin in the venom of fish-hunting cone snails represented the first example of the use of insulin as a weapon for prey capture. Cone snail toxins are highly stable and need to act very rapidly to allow a slow-moving snail to capture a fast-swimming fish. Because of these features cone snail toxins are ideal compounds for drug development. Unlike currently used insulin drugs, the insulins from cone snail venom do not form clusters and are likely to more readily lower blood glucose and disappear from the blood stream than human insulin. Thus, these compounds can directly inspire and inform on the generation of new prandial insulin drugs for T1D management.
Description of Project
Insulin is a hormone that is of critical importance for maintaining healthy blood sugar (glucose) levels in humans. Its secretion from the pancreas prevents blood glucose levels from getting too high (hyperglycemia). Type 1 diabetes (T1D) is a chronic condition in which the immune system destroys the cells of the pancreas that produce insulin. Currently, there is no cure for T1D, and the only effective treatment is daily insulin injections. The goal of insulin drug therapy is to achieve healthy blood glucose levels. This remains a major challenge because it is difficult to mimic the pancreas’ ability to readily sense the need for the right amount of insulin and to directly release insulin into the bloodstream where it can rapidly control glucose levels. Recent technological advances in designing artificial pancreas devices have the potential to significantly improve treatment regimes. Upon sensing high or low blood glucose levels these devices automatically inject insulin (and its counteracting hormone glucagon). Despite these promising developments, a major limitation of these closed-loop systems is that available insulin therapeutics are not fast enough to rapidly lower blood glucose and that they continue to exert their action for several hours after injection, often resulting in episodes of low blood glucose (hypoglycemia). Designing fast-acting insulin drugs has remained challenging because insulin form clusters with other insulin molecules (so-called hexamers) that very slowly travel through the body to reach their site of action. This slow process leads to a delay in blood-glucose control and a prolonged action of the insulin drug that remains close to the injection site. Until now, scientists have not been able to make a fast-acting insulin drug that does not form clusters.
New hope for solving this persisting problem came from our discovery that predatory marine cone snails use several different fast-acting insulins to rapidly induce low blood glucose in their fish prey. Unlike human insulin and current insulin drugs, the snail insulins do not cluster and can more readily reach their site of action. However, although the venom insulins can travel more rapidly through the body, they do not have the same potency as human insulin. In this project we will computationally design, produce and test modified versions of venom insulins that are fast-acting and have the same potency than human insulin and current insulin drugs. By doing so we aim to generate a ultrafast-acting T1D drug that will enable better control of blood glucose levels and be used in a closed-loop systems in the future.
Anticipated Outcome
At the end of this project, we anticipate having designed and generated a small set of 2-3 insulin drug leads that are fast-acting, have a shorter tail of action and may have improved stability profiles than existing T1D drugs. These drug leads will be subjected to preclinical testing to establish their safety and effectiveness for future clinical testing and use by people with T1D.
Relevance to T1D
In the absence of a T1D cure, closed-loop artificial pancreas devices hold great promise for changing the lives of people with T1D. These devices offer better control of blood glucose levels leading to fewer episodes of hyper- and hypoglycemia, which in turn leads to reduced risks of long-term diabetic complications. It is widely recognized that faster insulin analogs and those with a shorter tail of action will enhance the current performance of these closed-loop systems. By generating improved, venom-inspired insulin drug analogs for T1D this proposal addresses a persisting limitation in T1D management.