Why engineer peptide based pharmaceuticals? Shelf-life Pharmaco kinetics Physical and atic stability sta bility in ance France Excreton. Fitration- Reabsorption 4 Secret Convenience Easy to use Pharmacodyna availability Potenc S.C. degradation Tissue distribution S.C. uptake Non-invasive delivery
Why engineer peptide based pharmaceuticals? 11 Shelf-life Physical and chemical stability in drug product Pharmacokinetics Enzymatic stability Renal clearance Receptor clearance Bioavailability s.c. degradation s.c. uptake “Non-invasive delivery” Pharmacodynamics Potency Tissue distribution Convenience Easy to use
Core competency in taking proteins from molecule to market Mutation Half-life extension Acylation Sustained release Pegylation Liquid Modification Oral delivery ● Genetic ● Enzymatic ● Chemica E coli Prefilled pens Yeast Durable pens Mammalian cells Delive Infusion devices
Slide no 12 Core competency in taking proteins from molecule to market Mutation Pegylation Acylation Modification • Genetic • Enzymatic • Chemical Liquid Sustained release Half-life extension Prefilled pens Durable pens E.coli Yeast Mammalian cells Oral delivery Infusion devices
Main challenges for therapeutic peptides Most natural peptides are not applicable for convenient pharmaceutical treatment Main challenges to overcome Physical and chemical stabilit Enzymatic stability Bioavailability Pharmacokinetic profi Potency Route of administration should be included in design phase due to complementary challenges
Main challenges for therapeutic peptides • Most natural peptides are not applicable for convenient pharmaceutical treatment • Main challenges to overcome: • Physical and chemical stability • Enzymatic stability • Bioavailability • Pharmacokinetic profile • Potency • Route of administration should be included in design phase due to complementary challenges
Slide no 14 Slide no 14 Therapeutic Peptides Elimination Mechanism of clearence Proteolysis Renal excretion and metabolism Hepatic metabolism Receptor-mediated elimination Phagocytosis
Slide no 14 Date Slide no 14 Therapeutic Peptides Elimination • Proteolysis • Renal excretion and metabolism • Hepatic metabolism • Receptor-mediated elimination • Phagocytosis Mechanism of clearence:
slide Inhibition of renal clearance .Increasing size (not mass o Increase of negative charges Hydrodynamic Volume not absolute mass PEG interacts with water h PEG unit has 2-3 water molecules tightly associated - PEG appears to be 5-10 times larger than a protein of similar MI
Slide no 15 Inhibition of Renal Clearance O O O O O n O O H H O H H Each PEG unit has 2-3 water molecules tightly associated -> PEG appears to be 5-10 times larger than a protein of similar MW Hydrodynamic Volume not absolute mass PEG interacts with water: •Increasing size (not mass!) •Increase # of negative charges