Peptide Therapeutics

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  • Created by: LBCW0502
  • Created on: 13-11-19 16:11
Give examples of peptides approved by the FDA
Encallantide, telavancin, romidepsin, laraglutide, boceprevir, telaprevir, brentuximab vedotin, icatibat (table)
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State features of the peptides SWOT analysis - strengths
Good efficacy, safety and tolerability. High selectivity and potency. Predictable metabolism. Shorter time to market. Lower attrition rate. Standard synthetic protocols
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State features of the peptides SWOT analysis - weaknesses
Chemically and physically unstable. Prone to hydrolysis and oxidation. Tendency to aggregate. Shorter half-life and fast elimination. Usually not orally available. Low membrane permeability
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State features of the peptides SWOT analysis - opportunities
Discovery of new peptides including protein fragments. Focused libraries and optimised designed sequences. Formulation development. Alternative delivery routes. Multifunctional peptides
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State features of the peptides SWOT analysis - threats
Immunogenicity. New advancement in genomics, proteomics and personalised medicines. Price and reimbursement environment. Increasing safety and efficacy
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Describe features of peptide synthesis selectivity
Two amino acids, form peptide, join together (issue – amino group is + charged, not a nucleophile, delta + for C is small) – unreactive. Different combinations from two amino acids. Able to form tripeptides, polymers
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State features of peptide synthesis using protective groups (1)
Zwitterionic amino acids – 2 joined together, too many reactants involved • Protect N with a group so N doesn’t participate in the reaction (no longer zwitterionic). COOH – protection group added. One acid, one amine (with lone pair of electrons)
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State features of peptide synthesis using protective groups (2)
Make carbonyl more reactive. Able to make amide (COOH and NH2). Removal of protecting groups (deprotection)
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What are the requirements for protecting groups?
Easily introduced, stable to chemical reactions, easily removed. Dipeptide formation – 6 reactions for every step (inefficient process, low yield)
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Why is solid phase synthesis used?
Optimise reaction kinetics. Allows use of a large excess of reagents. Improving efficiency of many transformations. Purification of compounds bound to solid support from those in solution is accomplished by simple filtration
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Describe features of solid phase synthesis (1)
Bead resin, solid support, attach first amino acid onto the bead (S), lots of the second amino acid, make sure all beads react, wash out beads (drive reaction to 100% due to second amino acid being in excess)
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Describe features of solid phase synthesis (2)
Purification – wash solid support with a solvent, simple filtration, continue with next reaction
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Describe features of solid phase synthesis (3)
Resin – insoluble in the solvent (polystyrene with PEG), attach a linker (link peptide to support), anchor first amino acid, NPG (N alpha protecting group), one COOH reacts with linker, SPG (side chain protecting group)
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Describe features of solid phase synthesis (4)
Resin bead with first amino acid attached. Deprotection of NPG. Amino group on amino acid (attached to linker), wash. Another amino acid attaches to amino acid on the linker (activator acylation, repeat reaction until peptide is formed)
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Describe features of solid phase synthesis (5)
Formation from C-terminus to N-terminus. Agent to remove SPG and linker. Produce peptide
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Describe features of protecting groups (1)
Use an ester for COOH, use ether for alcohol (able to convert the groups back to COOH and alcohol)
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Describe features of protecting groups (2)
Amide – not a protecting group (reaction conditions are too harsh).
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Describe features of protecting groups (3)
Use a carbamate as a protective group for amine (carbamate – mixture of amide and ester), hydrolyse ester to give an amine with carbon dioxide (spontaneously loses carbon dioxide)
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Describe features of Fmoc amino acid
9-fluorenylmethoxycarbonyl amino acid (Fmoc amino acids) – not aromatic (needs 2 more electrons to become aromatic). Piperidine involved in reaction, elimination of dibenzofulvene, reaction of benzofulvene with piperidine. NPG formed (diagram). UV
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What are the concepts for aromaticity?
Planar (sp2 C), conjugation, 4n + 2 pi electrons where n is an integer
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What are acid labile protecting groups?
E.g. use of an ether/ester group mixture
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State features of peptide bond formation (1)
Activate COOH/form leaving group. Amide bond formed with DCC – N picks up proton, electrons to O, O attacks C, carbonyl is now reactive, amine can attack carbonyl (addition-elimination reaction), proton transfer, amide formed, O-acylurea, N-acylurea
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State features of peptide bond formation (2)
1-hydroxybenzotriazole suppresses N-acylurea (no longer used – explosive when dry) - diagram
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State the steps of peptide synthesis
N-deprotection, coupling/acylation (repeated steps until peptide formed), cleavage (remove reagents to give peptide)
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Which methods are used for purification and characterisation of the peptide?
HPLC, MS (high resolution), MALDI-TOF (peptide placed on plate, fire laser, ionisation of matrix, transferred to peptide, TOF related to mass). High yield - don't need to purify peptide
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What is hepcidin?
Peptide which regulates iron metabolism (solid phase synthesis, reduction, purification, folding, purification - peptide synthesis)
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What is LHRH? (1)
Luteinising hormone releasing hormone (hypothalamus LHRH, pituitary LH, testis, testosterone, activation of target genes, association with cancer) - potential LHRH agonist for treatment (8 residue peptide)
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What is LHRH? (2)
Formulations, polymer erodes, slow release of peptide, injection given monthly (also use in DM)
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Card 2

Front

State features of the peptides SWOT analysis - strengths

Back

Good efficacy, safety and tolerability. High selectivity and potency. Predictable metabolism. Shorter time to market. Lower attrition rate. Standard synthetic protocols

Card 3

Front

State features of the peptides SWOT analysis - weaknesses

Back

Preview of the front of card 3

Card 4

Front

State features of the peptides SWOT analysis - opportunities

Back

Preview of the front of card 4

Card 5

Front

State features of the peptides SWOT analysis - threats

Back

Preview of the front of card 5
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