There is a world-wide twin epidemic of obesity and Type 2 Diabetes (T2D), with an urgent need to find effective new drug treatments for inducing weight loss. Stable derivatives of the endogenous glucoregulatory hormone, glucagon-like peptide-1 (GLP1) are in clinical use for the treatment of T2D but are of equally great interest as an emerging treatment of obesity and of age-related neurodegenerative conditions including Parkinson's and Alzheimer's disease. Another glucoregulatory hormone, glucose-dependent insulinotropic peptide (GIP) has recently been shown to induce a synergistic profile of metabolic and neuroprotective benefit with GLP1 in animal studies. However, for GIP to be clinically useful for any of the envisioned combination treatments, e.g. to further enhance the weight loss induced by GLP1 based medications, GIP needs to be modified to confer protection from rapid enzymatic degradation in the blood stream. The applicants (Velum, Inc.) have access to a patent-protected novel strategy to make GIP fully resistant to its main inactivation mechanism of amino- terminal enzymatic cleavage, by attaching functionally well-tolerated decorations to the peptide's first amino acid. In this phase I application, they propose to apply this strategy, in conjunction with complementary modifications to stabilize GIP, with the goal of identifying a lead compound that holds promise for future development. In collaboration with Tufts University, where biological assessment of compounds will be performed, two Specific Aims will be pursued. Starting with a prototype stable GIP analogue that has already been engineered, VEL-42, Aim 1 is to further improve on this molecule by introducing alternative amino- terminal decorations and fatty acid acylations of other selected GIP residues. A total of 12 follow-up molecules to VEL-42 will be generated. These will be tested for agonist activity/receptor potency and enzyme stability in vitro, as well as for survival in the blood stream after subcutaneous injection in mice. Serum peptide levels will be followed using a sensitive bioassay that has been developed for this project to enable compound detection regardless of structural modifications. In Aim 2, to establish efficacy in a model of therapeutic application, two analogues with highest potency and stability will be selected for studying drug-induced weight loss in mice with diet-induced obesity. As the experimental paradigm, GIP analogues will be co-injected every third day over a three week period with a latest generation GLP1-based drug, thus enabling the detection of synergistic effects on weight loss and obesity-related hyperglycemia. It is anticipated that a candidate GIP analogue will be identified that can be developed in future Phase II studies as a companion drug for GLP1 agonists for the treatment of obesity and of neurodegenerative disease.
Public Health Relevance Statement: The proposed work will identify a candidate molecule that may evolve as a future treatment for obesity and of age-related neurodegenerative conditions including Parkinson's and Alzheimer's disease. Using a new chemical strategy, a gut hormone that naturally helps maintain normal blood sugar and body weight will be stabilized for therapeutic application. This drug, when given as a combination treatment, will synergistically enhance the weight-reducing effect of currently emerging medications with additional neuroprotective potential.
Project Terms: Clinical; Phase; Biological; Physiologic; Physiological; Mature fat cell; Mature Lipocyte; Lipocytes; Fat Cells; Adipose Cell; Adipocytes; Chemicals; Evaluation; Blood Serum; Serum; analog; Agonist; Collaborations; Therapeutic; Metabolic; Companions; Stream; Clinic; Overweight; Over weight; Neurodegenerative Disorders; neurodegenerative illness; degenerative neurological diseases; degenerative diseases of motor and sensory neurons; Neurologic Degenerative Conditions; Neurodegenerative Diseases; Neural degenerative Disorders; Neural Degenerative Diseases; Nervous System Degenerative Diseases; Degenerative Neurologic Disorders; Degenerative Neurologic Diseases; interest; peptide analog; receptor; Receptor Protein; Animal Model; model organism; model of animal; Animal Models and Related Studies; novel; new technology; novel technologies; Regulation; Modeling; Sampling; Adverse effects; treatment adverse effect; therapy adverse effect; side effect; Treatment Side Effects; insulin secretion; polypeptide; Address; liraglutide; Detection; High Prevalence; in vivo; Endocrine Pancreas Secretion; Pancreatic Endocrine Secretion; C57BL/6 Mouse; Modification; followed up; follow up; Active Follow-up; follow-up; developmental; Development; pathway; Pathway interactions; obesity treatment; age dependent; age related; neglect; clinical efficacy; novel strategy; novel approaches; new approaches; novel strategies; Population; NH2-terminal; N-terminal; resistant; Resistance; novel therapy; novel drugs; novel drug treatments; next generation therapeutics; new therapy; new therapeutics; new drugs; new drug treatments; novel therapeutics; prototype; drug candidate; Phase I Study; phase 1 study; phase II study; phase 2 study; Drug Targeting; metabolic profile; therapeutic candidate; translational spectrum; translational pipeline; Acylation; Aging; Alzheimer's Disease; senile dementia of the Alzheimer type; primary degenerative dementia; dementia of the Alzheimer type; Primary Senile Degenerative Dementia; Alzheimers disease; Alzheimers Dementia; Alzheimer's; Alzheimer syndrome; Alzheimer sclerosis; Alzheimer disease; Alzheimer Type Dementia; Alzheimer; Amino Acids; aminoacid; Animals; Biological Assay; Biologic Assays; Bioassay; Assay; Biological Availability; Physiologic Availability; Biologic Availability; Bioavailability; Blood; Blood Reticuloendothelial System; Blood Glucose; Blood Sugar; Body Weight; Cardiovascular Diseases; cardiovascular disorder; Cell physiology; Subcellular Process; Cellular Process; Cellular Physiology; Cellular Function; Cell Process; Cell Function; Cells; Cell Body; Clinical Trials; Comorbidity; co-morbidity; Diabetes Mellitus; diabetes; Non-Insulin-Dependent Diabetes Mellitus; type two diabetes; type II DM; type 2 DM; maturity onset diabetes; ketosis resistant diabetes; adult onset diabetes; Type II diabetes; Type II Diabetes Mellitus; Type 2 diabetes; Type 2 Diabetes Mellitus; T2DM; T2D; T2 DM; Stable Diabetes Mellitus; Slow-Onset Diabetes Mellitus; Noninsulin Dependent Diabetes Mellitus; Non-Insulin Dependent Diabetes; NIDDM; Maturity-Onset Diabetes Mellitus; MODY; Ketosis-Resistant Diabetes Mellitus; Adult-Onset Diabetes Mellitus; Diet; dietary; Dipeptidyl Peptidases; Dipeptidylpeptide Hydrolases; Dipeptidyl Aminopeptidases; Pharmacotherapy; drug treatment; Drug Therapy; Pharmaceutical Preparations; drug/agent; Pharmaceutic Preparations; Medication; Drugs; Engineering; Enzyme Stability; Epidemic; Fatty Acids; Future; Gastric Inhibitory Polypeptide; gastric inhibitory peptide; Glucose-Dependent Insulinotropic Peptide; Glucose-Dependent Insulin-Releasing Peptide; Glucose; Dextrose; D-Glucose; Goals; Half-Life; Health; Homeostasis; Physiological Homeostasis; Autoregulation; Hormones; Therapeutic Hormone; Endocrine Gland Secretion; Hyperglycemia; hyperglycemic; In Vitro; Industry; Subcutaneous Injections; Intestinal Mucosa; Kidney; renal; Kidney Urinary System; Lead; heavy metal lead; heavy metal Pb; Pb element; Ligands; Light; Photoradiation; Mus; Murine; Mice Mammals; Mice; Nerve Degeneration; neuronal degeneration; neurological degeneration; neurodegenerative; neurodegeneration; neural degeneration; Neuron Degeneration; Obesity; obese population; obese person; obese people; obese; corpulentia; corpulency; corpulence; adiposity; Parkinson Disease; Primary Parkinsonism; Parkinsons disease; Parkinson's disease; Parkinson's; Parkinson; Paralysis Agitans; Legal patent; Patents; Patients; Peptide Hydrolases; Proteolytic Enzymes; Proteinases; Proteases; Protease Gene; Peptidases; Esteroproteases; Peptides; Pharmacology; Physiology; Safety; Testing; Twin Multiple Birth; Twins; United States Food and Drug Administration; USFDA; Food and Drug Administration; Universities; Body Weight decreased; wt-loss; body weight loss; Weight Reduction; Weight Loss; Weight; Work; glucagon-like peptide 1; GLP-1; Generations; Measures; Health Care Costs; Healthcare Costs; Health Costs; base; improved