MEDCH 327: Introduction to Peptide-Based Therapeutics

Introduction to Newer Therapeutic Modalities

  • Arun's background: Faculty member involved in both lab research and development/engineering of therapeutics.
  • Focus: Newer classes of therapeutic modalities, specifically therapies derived from peptide hormones.

Traditional Small Molecule Drugs vs. Biologics

  • Traditional small molecule drugs:
    • Examples: Aspirin, Lipitor.
    • Size: Typically smaller than 1000 Daltons.
    • Administration: Often administered orally.
    • Cellular access: Generally effective at entering cells and engaging targets.
  • Biologics:
    • Definition: Molecules derived from peptides, proteins, or cell-based therapies.
    • Examples: antibodies.

Features of Small Molecule Drugs vs. Biologics

  • Peptide and protein-based drugs (biologics):
    • Size and binding: Larger size allows for high binding affinity and selective binding.
    • Example: Antibodies bind tightly to specific molecules.
    • Cellular access: Antibodies are too large to enter cells.
  • Middle ground: Potential for molecules that combine the advantages of both small molecule drugs and peptides.
    • Characteristics: Tight, selective binding, oral dosing, and cellular access.
    • Design of therapeutic methods: Gaurav will provide more detail on design later in the quarter.

Peptide Hormone-Based Drugs

  • Source: Utilizing peptide hormones naturally produced by the body.
  • Production: Various organs produce peptide hormones, playing important roles in metabolism.
  • Examples:
    • Insulin and incretins.
    • Growth and development: Growth hormone.
    • Blood pressure and renal function.
    • Mood and cognition: Oxytocin.
  • Function: Peptide hormones act as signaling molecules in the bloodstream.
  • Case studies: Focus on insulin, incretins, and growth hormones.

Case Study: Insulin

  • Key questions:
    • Biological function: What does insulin do?
    • Therapeutic use: How is it used in therapy?
    • Cost: Why is insulin so expensive?

Context on Metabolism

  • Metabolic pathways: The body constantly regulates metabolites through intricate pathways.
  • Peptide hormones: Play a crucial role in metabolic regulation.

Levels of Glucose

  • Blood glucose regulation: Ideally maintained in a narrow range (4-7 millimolar).
  • Healthy individual:
    • Baseline: ~5 millimolar.
    • Post-meal spike: Small spike after meals, returns to baseline.
  • Individual with poorly controlled type 2 diabetes:
    • Baseline: Higher than normal.
    • Post-meal spike: Much higher and longer-lasting spikes.

Hormones Regulating Blood Glucose

  • Insulin: Lowers blood glucose levels when they rise.
  • Counterinsulin hormones (e.g., glucagon): Raise blood glucose levels when they drop.
  • Epinephrine (adrenaline):
    • Function: A fight-or-flight hormone that ensures adequate blood glucose during stress.
    • Context: Released during scary situations.

Production of Insulin and Glucagon

  • Pancreas: Produces both digestive enzymes and hormones.
  • Islets of Langerhans: Clusters of endocrine cells within the pancreas.
    • Alpha cells: Produce glucagon.
    • Beta cells: Produce insulin.
  • Reciprocal regulation: Insulin and glucagon production are reciprocally regulated.

Metabolic Processes After a Meal

  • Initial phase: Burning glucose from the meal (first few hours).
  • Glycogen use: After ~4 hours, the body uses glycogen (branched glucose chains in the liver and muscles) as an energy source for ~12 hours.
  • Gluconeogenesis: If starvation is prolonged, glucose is synthesized from other molecules (amino acids, pyruvate, lactic acid, glycerol).
  • Starvation phase: Prolonged starvation leads to the use of ketone bodies (small, four-carbon molecules synthesized from fats, sugars, or amino acids) as an energy source.
  • Brain's glucose requirement: The brain still needs some glucose to function, even during starvation. Lack of glucose leads to hypoglycemic coma.
  • Low carb diets: Mechanism involves forcing the body to synthesize ketone bodies and break down fat.

Overview of Metabolic States

  • Well-fed state: Burning dietary glucose.
  • Overnight fast: Burning glycogen.
  • Starved state: Relying on ketone bodies and fatty acids.

Diabetes Mellitus

  • Definition: Excessive urine production (polyuria) with glucose in the urine.
  • Cause: High blood glucose levels spilling into the kidneys.
  • Types: Type 1 and Type 2 diabetes are distinct conditions.

Type 1 vs. Type 2 Diabetes

  • Type 1 Diabetes:
    • Nature: Autoimmune disease where the body destroys beta cells in the pancreas (insulin production problem).
  • Type 2 Diabetes:
    • Nature: Metabolic disorder where cells become less sensitive to insulin signaling (insulin resistance) due to prolonged overnutrition and underactivity.

Gestational Diabetes

  • Development: Insulin resistance during pregnancy due to hormonal changes.
  • Understanding: Less understood aspect of women's health.

Details on Type 1 Diabetes

  • Previous term: Often called juvenile diabetes due to earlier onset.
  • Mechanism: Immune system attacks the pancreas and islets of Langerhans, causing inflammation (insulitis) and beta cell loss.
  • Symptom onset: Symptoms appear after ~80% of beta cells are destroyed.
  • Metabolic state: Resembles a starved state with high ketone bodies, fatty acids, and blood glucose levels.
  • Glucagon effect: Dominated by the effects of glucagon due to little to no insulin.
  • Consequences: Untreated, leads to heart disease, kidney disease, retinopathy, neuropathy, and reduced lifespan.

Details on Type 2 Diabetes

  • Insulin resistance: Cells don't take up glucose properly in response to insulin.
  • Correlations: Linked to heart disease, stroke, Alzheimer's disease, and other metabolic disorders.

Pancreatic Changes in Type 2 Diabetes

  • Beta cell stress: Pancreas works overtime to produce insulin, but cells become stressed.
  • IAPP secretion: Beta cells secrete islet amyloid polypeptide (IAPP) along with insulin.
    • Amylin is aggregation prone.
  • Aggregation: Excess IAPP aggregates, killing beta cells.
  • Vicious spiral: Insulin resistance leads to beta cell stress and death, further reducing insulin production.
  • Insulin levels: Initially higher than normal (pancreas trying to compensate), then drop over time due to beta cell failure. So, higher insulin levels initially, leading to a drop.

Insulin as a Therapy

  • Discovery: Banting and Best discovered insulin over 100 years ago.
  • Treatment: Used pancreatic extracts from animals to treat children with type 1 diabetes.
  • Extract administration: Decreases blood glucose and the amount of glucose excreted in urine.
  • Patent sale: Banting and Best sold the insulin patent to the University of Toronto for $1.
    • Ensured availability to humankind.

How the Insulin Response Works

  • Proinsulin processing: Beta cells produce proinsulin, which is cleaved into insulin (A and B chains linked by disulfide bonds).
  • Hexamers: Insulin monomers are packaged into hexamers within secretory granules, with amylin also present.
  • Glucose spike trigger: Rising blood glucose causes glucose to enter beta cells and raise ATP levels.
  • ATP-gated channels: Increased ATP triggers a signaling cascade, releasing secretory granules into the bloodstream.
  • Biphasic response: Quick burst of insulin (~15 minutes after a meal), followed by a slower, sustained release.

Effective Insulin Therapy

  • Goal: Replicate the physiological insulin response.
  • Benefits: Better blood glucose regulation, reduced risk of hyperglycemia (long-term health consequences) or hypoglycemia (insulin overdose).
  • Modifications:
    • Sequence changes.
    • Formulation changes (adjuvants).
    • Chemical modifications (e.g., lipid tails).
  • Monomer vs. hexamer: Fast-acting forms favor the monomer (active state), slow-acting forms favor the hexamer.
  • Spectrum of insulins: Ranging from fast-acting to long-acting.

Types of Insulin Modifications

  • Objective: Giving the patient a physiological biphasic response through the insulin drug.
  • Different insulins: Will give different types of responses (long acting, fast acting).
  • Fast acting insulins.
  • Regular acting insulins: Natural insulin.
  • NPH: An older sustained response.
  • Long-acting forms: Dedomir and glargine is a 24-hour baseline.
  • Combination: Long acting insulin to take care of the plateau and fast acting following a meal.

Insulin Modifications

  • Equilibrium: Monomer will slowly fall apart held with covalent bonds.
  • Stickiness: Modifications to insulin allows for bindings to serum and sustained release.

Specific Insulin Modifications

  • Fast-acting forms: Destabilize the hexamer for faster release.
    • Insulin lispro: Proline and lysine are switched.
  • Long-acting forms: Designed for sustained response.
    • Glargine: Asparagine converted to glycine, arginates added to the C-terminus.
    • Detemir: Threonine deleted, myristic acid added.

Insulin Prices

  • Chemical distinction: Each form of insulin is chemically distinct, approved separately, and priced as a new drug.

  • Patient stability: Patients who have success can experience risks when switching to less ideal forms.

  • The capitalism greed angle is a really big part of it.

    GLP-1 Receptor Agonists (Incretins)

  • Beta cells: Have receptors for glucagon, GLP-1, GLP-2, and GIP, which regulate insulin production.

  • GLP-1 and GLP-2: Enhance insulin and downregulate glucagon production. Produced in the intestine.

  • Signaling roles: Also have roles in the heart, muscle activity, appetite, and cognition.

  • Short half-life: GLP-1 and GLP-2 have short half-lives (minutes) for short-term signaling.

  • Nomenclature: GLP-1 and GLP-2 downregulate glucagon, despite being "glucagon-like peptides." Produced from the same precursor, proglucagon.

    GLP-1 Analogs

  • Goal: Leveraging signaling pathways with longer-lived molecules.

  • Enzyme catabolization: GLP-1 has a short half-life due to cleavage by DPP-4 at position two.

  • Naturally-derived peptides: Exenatide is produced by the Gila monster and has similar effects to GLP-1 (increase insulin and decrease glucagon).

  • Lysine: Additions of lysine lead to longer duration in the body.

Semaglutide

  • Fatty acid: Attaching an 18-carbon fatty acid chain gives a half-life of multiple days.
  • Liraglutide is another molecule with the addition of fatty acid tail.
  • Albaglutide: Two copies of GLP-1 where there is a fusion protein of albumin.
  • Dulaglutide: Two copies of GLP-1 fused to an antibody fragment.

Oral Formulations

  • Oral Delivery: Transcellular absorption of the peptide.

Potential Black Market

  • Black market: Off brand Ozempic that has not be authorized can lead to death.

Biosimilars

  • Complex manufacturing: Complex to make due to composition.
  • Providers: Must sign off on change from the reference product to the Biosimilar.

Costs

  • Biosimilar is likely cheaper than the reference product.