BCH3052 Lecture 18: Redesigning Proteins for Improved Human Therapy
Lecture 18 – Redesigning Proteins for Improved Human Therapy
• To improve stability (shelf life or in vivo stability)
o To permit oral administration
• To improve activity/specificity for target
• To improve all aspects of ADME (Absorption, distribution, metabolism and
excretion)
Case Study: Insulin
• Insulin: protein hormone produced in pancreas
• Regulates carbohydrate uptake and release
• Used medically in some forms of diabetes mellitus (injectable molecule)
• Diabetes mellitus
o Type 1: patients have no insulin
▪ Rely entirely on
subcutaneous injections for
survival
o Type 2: patients either have low
insulin or insulin resistance
▪ Require insulin
administration as well
• Binds to insulin receptor → influx of
glucose from blood, glycogen synthesis, glycolysis and fatty acid synthesis
• Structure
o Small protein made of two chains
▪ Alpha residue: 21 chains
▪ Beta residue: 30 chains
• Linked together by 3 disulphide bonds
▪ Forms trimers of dimers
• Initial source of insulin for clinical use in humans was sourced from cow, pig
or fish pancreases
o Get e.colli to make protein for us
• Inulin is secreted by the pancreas (immediate response) after a meal in
response to the rise in plasmas glucose
o Helps maintain the plasmas glucose concenetration throughout the day
o Pattern is difficult to replicate by insulin injection (problem 1)
▪ Need to anticipate a meal
▪ Injected insulin peaks in plasma 1-3 hours after injection and
returns to basal levels in 6-8 hours
▪ Problem 2: storage life: insuline changes during storage
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