Peptide drugs and therapeutics
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27 Terms
what is the isoelectric point?
the pH at which the positive equates to the negative charge
what is special about histidine?
it doesn’t have a charge
what are the 5 amino acid groups?
o Nonpolar, aliphatic R groups
o Polar, uncharged R groups
o Aromatic R groups
o Negatively charged R groups
o Positively charged R groups
which 2 amino acids are positively charged?
lysine (lys)
arginine (arg)
which 2 amino acids are are negatively charged?
aspartic acid (asp)
glutamic acid (glu)
what happens id pH>pKa?
compound is deprotonated
how do you calculate the isoelectric point for non-polar amino acids without ionisable side chains?
o pI = (pKa1 + pKa2) / 2
§ Here, the net charge is 0
§ The AA is soluble in water
§ AA does not migrate in the electric field, which is important in electrophoretic separation of peptides
what does bradykinin do?
inhabits the inflammation of tissue
what does vasopressin do?
regulates bodily retention of water and is also released in response to stress
what does oxytocin do?
induces labour and stimulates milk production
what is aspartame?
NutraSweet
what are the strengths of peptide SWOT analysis?
o Good efficacy, safety and tolerability
o High selectivity and potency
o Predictable metabolism
o Shorter time to the market
o Lower attrition rate
o Standard synthetic protocols
what are the weaknesses of peptide SWOT analysis?
o Chemically and physically unstable
o Prone to hydrolysis and oxidation
o Tendency to aggregate
o Shorter half-life and fast elimination
o Usually not orally available
o Low membrane permeability
what is the opportunity of peptide SWOT analysis?
o Discovery of new peptides
o Focused libraries
o Formulation development
o Alternative delivery routes
o Multifunctional peptides and conjugates
what are the threats of peptide SWOT analysis?
o Immunogenicity
o New advancement in genomics and proteomics
o Price and reimbursement
o Increasing safety and efficacy requirements
why can’t you react two amino acids randomly to produce a primary sequence?
- Reacting two amino acids randomly may produce a different primary sequence in the peptide
o This means that it may not bind to the target receptor, making it a non-functional drug
o Protecting groups need to be used to make peptides
what is used to make a specific protein using amino acids?
protecting groups
how do protecting groups work?
- protect’ the amino group on one amino acid and ‘protect’ the carboxyl group on the other amino acid, to prevent them from reacting so the desired terminals of each amino acid react instead
o This is then followed by the removal of the protection factor added to one of the terminals, as this allows for the freedom of a NH or COO to react further
what is the octagonal protecting group strategy?
o The carboxylate protecting group must be stable in the reaction conditions for the removal of the a-amino protecting group and vice versa
what are the protecting group types?
o Convert carboxylic acids and alcohols into esters – via ester hydrolysis
o Convert carboxylic acids and alcohols/thiols into esters – via ether hydrolysis
o Convert amines to a carbamate – via ester hydrolysis
what are the different amine protection types?
o Use of a tertiary butyloxycarbonyl alanine (BOC) and is removed for trifluoro acetic acid (mild acid)
o A benzoyloxycarbonyl alanine can also be used (Z) and is removed by a strong acid hydrogen fluoride
o A 9-Fluoroenylmethoxycarbonyl (Fmoc) can also be used and is removed by a base, piperidine
how is a carboxylic acid activated?
- Activation involves conversion of the hydroxyl group of a carboxylic acid into a good leaving group
o Reaction of carboxylic acid + primary amine Complicated
how does amide bond foration occur with DCC?
DCC reacts with carboxylic acid (Acting as a base) to form an amide
How is a tripeptide formed?
- Reaction of carboxylic acid with a primary amine with Boc protection
- This forms amide bond formation (DCC)
- Boc deprotection occurs to form Trifluoroacetic acid
- Amide bond formation (DCC) (baso reacting again with another peptide)
- Removal of all protecting groups (The O and N gain charges at the terminals, becoming NH3+ and O-)
what are the key principles in solid phase synthesis?
- In the synthesis of proteins, time consuming purification steps should be avoided until the very end of the synthesis
- Excess reagents are used to drive the reaction in the forward direction and increase the rate of reaction
o The excess reagents and by-products are removed by filtration as to not interfere with subsequent coupling steps
o Peptides and proteins up to ~100 residues long are synthesised on a solid, insoluble polymer support
o Purification is accomplished after each step by a simple wash and filtration
what are the steps in solid phase synthesis?
o Deprotection with piperidine and wash
o Acylation with excess amino acid
o Repeat deprotection and acylation until peptide is formed
o Remove the SPG and resin cleavage and linker (polyethylene) (trifluoracetic acid)
o NPG - Na protection group (Fmoc)
o SPG – side chain protecting group (Boc, tBu)
what is the benefit of automated peptide synthesis?
increases the yield