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Peptides as Drugs


Acts at GPCR in the liver to facilitate gluconeogenesis and mobilization of glycogen stores ... induce insulin secretion, decrease in gluconeogenesis ... – PowerPoint PPT presentation

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Title: Peptides as Drugs

Peptides as Drugs
Protein Primary Structure and Peptide Bonds
  • Proteins primarily exist as L-a amino acids
  • Amino acids are linked via peptide bond
  • Very stable due to resonance
  • Peptide bonds are susceptible to hydrolysis by
    proteases and peptidases
  • Aminopeptidase, carboxypeptidase, endopeptidase,
    trypsin, chymotrypsin, pepsin
  • Protection of peptide bond gt stability

Amino Acids
  • Non-Polar, Non-charged side chains
  • Gly, Phe, Ala, Val, Pro, Met, Leu, Ile
  • Polar, Non-charged
  • Ser, Tyr, Cys (participates in disulfide bond
    formation), Trp, Thr, Asn (can be N-glycosylated)
  • Polar, Charged
  • Basic ( charged) Arg, Lys, His (50 charged at
    physiological pH, what is the pKa?)
  • Acidic (- charged) Asp, Glu
  • The sequence of a.a. in a peptide determines a
    proteins characteristics and activities.

Hierchical Structure of Proteins
  • Primary peptide
  • Covalently linked aa. through peptide bonds
  • Secondary polypeptide fold up according to
  • Alpha Helix
  • Beta sheet
  • Also consist of turns, kinks, and loops (i.e.
  • Tertiary 3D, native structure of single
    polypeptide or protein
  • Quaternary single polypeptides associate with
    each other
  • forming larger protein complexes of geometrically
    specific arrangements

Secondary Structures
  • Alpha Helix
  • Beta Sheets

- Contains mostly hydrophobic residues and the
backbones are fully H-Bonded - The amphipathic
beta sheet contains alternating polar and
non-polar R groups - Antiparallel N-terminus
coincides with the C-terminus of the adjacent
chain H-bond not tilted - Parallel N-terminus
coincides with the N-term of the adjacent chain
H-bond tilted
- The alpha helix repeats every 3.6 residues -
The backbone is about 5Å in diameter - It has a
hydrophobic and non-polar center with hydrophilic
and polar R chains - What drives protein folding
is the hydrophobic effect
Secondary Structures (cont.)
  • Loops
  • Can often find pro and gly in this region
  • Kinks
  • Prolines cannot hydrogen bond gt forms a kink
  • Links
  • Stabilizes turns via Cys-Cys disulfide bond

Post-Translational Modifications
  • Pyroglutamyl
  • Addition of glutamate to N-term
  • Carboxamides
  • Amide at the carboxy term
  • Slow degradation, prolonged T1/2
  • Cyclization
  • Ex. Cys-Cys in insulin
  • Internal amino acid modifications
  • Ex. hydroxylation of proline
  • Glycosylation
  • O and N-glycosides

Biosynthesis of Peptide Hormones and Processing
into Active Forms
Ex. Parathyroid Hormone
  • Biosynthesis
  • Pre-pro sequence leader sequence, rich in
  • Pre-pro PTH -gt cleaved -gt Pro PTH -gt cleaved -gt
    PTH (84 residues) -gt post translational
  • PTH is packaged in secretory granule stored at
    cytoplasmic matrix gt they are preformed
  • They will be secreted when needed
  • Processing
  • Pre-pro PTH -31 -7
  • Pro PTH -6 -1
  • PTH 1 84
  • Cleavage of Pre-Pro PTH into Pro PTH and PTH is
    tryptic cleavage (recalling that trypsin can
    cleave the basic residues such as Lys and Arg)

Address, Message, Potentiator
  • PTH must bind to PTH receptor and binding must
    result in conformational change
  • Must have sequence to bind to receptor gt address
  • Another sequence to signal its presence gt
    messenger sequence
  • Another sequence that potentiate activity or
    potency gt potentiator sequence

Address, Message, Potentiator (Cont.)
  • Active Sequence 134 aa
  • More conserved amongst species with few and minor
    conservative changes
  • 2527 aa is very important, loss of activity when
  • Potentiator sequence 1618aa
  • Variable region amongst different species
  • Differences in activities can be observed by
    digesting the peptide into different lengths
  • 134aa full biological activity observed
  • 126aa loss of activity due to interruption of
    the 3 important aa sequence (2527)
  • 234 and 334aa loss of activity observed gt
    first 2aa may have some importance gt potential
    messenger sequence.
  • PTH 1434 is likely to be the address sequence
    since it binds to the receptor and acts as an

Insulin, Diabetes, and the Antidiabetic Drugs
  • Secreted by the a pancreatic cells
  • Function
  • Elevation of blood glucose via mobilizing glucose
  • 29 aa. Peptide
  • Pro-glucagon 150 a.a. long
  • Processed in pancreatic a cells to generate the
    active peptide
  • Use
  • Acts at GPCR in the liver to facilitate
    gluconeogenesis and mobilization of glycogen
  • Can be used to treat severe hypoglycemia in Type
    1 Diabetics

Incretins GLP-1
  • Differential processing of glucagon in small
    intestine yields GLP-1 (truncated GLP)
  • Released upon food ingestion and sensing of sugar
  • Function
  • Promotes insulin synthesis/secretion, glucagon
    inhibition, increase in satiety, and slows
    gastric emptying
  • Inactivated by DPP IV via cleavage of GLP-1
  • Byetta (Exenatide) BID SC Inection
  • Modified form of Exentin-4 (GLP-1 analogue
    produced by Gila Monster)
  • GLP-1 Agonist
  • Extended half life and DPP IV resistance
  • Help regenerate ß Cells and inhibit apoptosis of
    ß cells
  • Associated with weight loss without association
    with hypoglycemia
  • Liraglutide QD SC Injection
  • Modified analogue of GLP-1
  • Have increased T1/2 due to increased
    lipophilicity of FA gt binds to albumin

Incretins DPP IV Inhibitors
  • DPP IV readily inactivates GLP-1 gt regulate
    glucose homeostasis
  • Diabetic patients have an increase in DPP IV
    inactivation of GLP-1
  • DPP IV Inhibitors Gliptins
  • Inhibits DPP IV gt Increase in T1/2 of GLP-1
  • Approved Sitalgliptin (Januvia)
  • In the pipline Vildagliptin (Galvus),

  • Produced by pancreatic ß cells
  • Produced initially as Pro-insulin C-peptide A
    chain B chain
  • Processed intracellularly to removed the
    connecting peptide and 4 additional a.a. gt
    Yielding A Chain and B Chain linked by disulfide
  • Processing machineryfor pro-insulin is
  • Insulin is preformed -gt packaged into golgi gt
    stored in ß cells
  • Sequence conserved in human, bovine, and porcine
    with minimal a.a. changes
  • Changes mostly occur in a.a. 810 of A Chain and
    amine (a.a. 15) and carboxy (a.a. 28 29)
    terminus of B Chain
  • Both bovine and porcine insulin have been used
    for diabetic patients
  • Patients using human insulin show fewer warning
    signs of hypoglycemia due to excess insulin

Insulin (Cont.)
  • Secondary and Tertiary Structure
  • A Chain 2 alpha helices that are antiparallel
  • B Chain Helix Elbow Beta Turn
  • Arm region hydrophobic interaction between
    monomers -gt H-bond form at interface gt
  • Dimer-Dimer association gt Hexamer
  • Insulin is stored as hexamer in storage cells
  • 2 Zn stabilizes the hexameric form
  • Only monomer can interact with receptor
  • Inversion of B29 Lys and B28 Pro -gt Change in
    configuration -gt dimer formation of insulin
    sterically inhibited gt exist as monomeric form
  • Lispro is acting insulin because theres no dimer
    dissociation step. It also does not associate
    with Zn in the formulation

Insulin (Cont.)
  • On Receptor…
  • When insulin binds to insulin receptor -gt
    autophosphorylation of receptor and
    phosphorylation of IR1, IR2gt transduction
  • Receptor is a dimeric tyrosine kinase receptor
  • Cortisol lowers affinity of insulin for receptor
    gt potential risk of diabetes
  • Control of Insulin Release of ß Cells
  • At rest low ATP -gt Kchannel remains open and
  • Cell is fully polarized gt negative cell
    potential and low insuling release
  • High glucose glucose causes an increase in
    intracelluar ATP -gt K channel closes -gt
    depolarization -gt Ca2 influx gt insulin release
  • Sulfonylurea antagonizes K Channel -gt maintains
    depoloarization gt increase in insulin release

Insulin (Cont.)
  • Function
  • In Liver
  • Inhibits glycogenolysis, conversion of fats into
    keto acids, and conversion of a. a. to glucose
  • Promotess glucose storage as glycogens, increase
    TG synthesis and VLDL formation
  • In Muscle
  • Increase protein and glycogen synthesis
  • In Fat
  • Increases TG storage

  • 1st Generation

MOA Antagonizes ATP depedend K Channels gt
induce insulin secretion, decrease in
gluconeogenesis All have similar
efficacy Duration of action differ because of
the way drugs are metabolized
  • 2nd Generation
  • Meglinides

Most Potent
Both classes have same MOA as 1st Generation
Sulfonylurea Longer acting and rapid onset
MOA Decrease in hepatic glucose output, decrease
in insulin resistance (thought to be due to
inhibition of gluconeogenesis) Excreted from
kidney, Highly bioavailable No Hypoglycemia SE
Acarbose and Amylin
  • Acarbose

MOA delays carbohydrate digestion and slows
glucose absorption in small intestine SE GI
(bloating and gas
  • Amylin (Pramlintide)

MOA Amylin analogue, act as an antagonist that
inhibits glucagon release by liver, reduces
appeitite. Combo with Insulin
  • MOA PPAR? agonist
  • Regulate glucose via nuclear interaction with
  • Increase expression of genes responsible for
    insulin release, f.a. oxidation, and insulin
  • Decrease expression of genes responsible for
    lipid production
  • Combo with Insulin

Thyroid Hormone
Outer Ring
Inner Ring (Tyr)
  • All thyroids are produced from Tyr by iodination
    and dimerization
  • Thyroglobulin Iodinates and acts as a storage
    of thyroid in colloids
  • Initially made as T4, the inactive form -gt
    deiondination from the periphery gt T3 (active
  • T4T3 51 gt most thyroids in body are not
  • rT3 is dominant in placenta of fetus, active
    form in developing fetus
  • No biological activity in adults (notice the
    different iodination sites?)
  • About 1/3 of T4 are converted to T3 and 40 of
    T4 are converted to rT3

Thyroid Hormone Plasma Binding and Transport
  • Thyroid Binding Protein
  • Carries 7080 of secreted thyroid hormone
  • 75 of T4 binding
  • tight binding
  • Thyroxine-Binding Prealbumin
  • Carries 1015 of thyroid hormone
  • 1015 of T4 binding
  • Low binding affinity
  • Serum Albumin
  • Carries remainder of secreted thyroid hormones
  • 510 of T4 binding, 1015 of T3 binding
  • lowest binding affinity for the hormones
  • Note once thyroid binds to the binding proteins,
    it cannot be deiondinated or metabolized

  • L-Tyr is the active form gt stereoselective (at
    the chiral carbon)
  • Phenol gp is essential
  • Provides H-bonding to the receptor
  • Rings must be perpendicular to each other
  • I3 and I5 interact with receptor
  • Also prevents rotation of the outer ring gt
    required for binding of receptor
  • Perpendicular orientation sensitive to bridging
    atom linking rings (O gt S, CH2)
  • Substitution at C3 and C5 with halogen or
    nonpolar methyl gt can cross placenta
  • 4 requires OH, NH2
  • T4 contains I in this position -gt cannot fit into
    receptor gt inactive
  • Most substitutions at C3 and C5 that is isoteric
    to I (halogen, methyl) and nonpolar will have
    some activity

Thyroid Hormone Antagonists and Agonists
  • Receptor specific
  • TRa cardiac stimulation
  • TRß cholesterol and energy metabolism
  • GC-1 TRß specific gt decrease in plama
    cholesterol level
  • T3 Non-specific
  • Agonists
  • Levothyroxine (T4) slower onset than T3 gt
    longer T1/2
  • Liothyronin (T3) rapid onset of action, not
  • Liotrix mixture of T4 and T3 (41)gt resemble
    natural form in body
  • Thyroid dessicated Theyroid gland from animal

Both Regulate Developement
Antithyroid Agents
  • Match the molecule above to the MOA
  • Thyroid peroxidase inhibitor
  • Inhibit Thyroid cardiac response
  • Inhibit iodine uptake
  • Inhibit peripheral deiondonases
  • Answer
  • Thioamides A, D
  • Beta Blocker C
  • Anion Inhibitors E
  • Iodinated contrast Media B