BCH3052 Lecture 17: Peptide Discovery and Development as Lead Drugs
25 May 2018
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Lecture 17 – Peptide Discovery and Development as Lead Drugs
Peptide
• Short chains of amino acids – less than 50 amino acids long
• May occur naturally from three sources:
o mRNA translated peptides
o Non-ribosomal peptides (produced by unicellular organisms, plants
and fungi)
o As a result of cleavage or proteolytic digestion of proteins
• Can be made synthetically
• Can have potent and specific activities – potential in development of novel
therapeutics
• E.g. Melittin from honey bee
o 26 residue peptide isolated from honey bee venome
o Possesses potent antimicrobial and haemolytic properties
o Exists in solution in equilibrium between unstructured
monomer and alpha-helix
▪ Hydrophobic face of helix
o Interact with lipid bilayers, or membranes with helical
axis parallel to membrane surface
o Reorientates to completely destroy the membrane bilayer
o Can be antimicrobial
▪ Able to kill bacteria but not interact with
eukaryotic cells
▪ Testing to see wehther antimicrobial and
haemolytic properties are separable
• E.g. Cyclosporin from fungus
o Example of a non-ribosomal peptide
o Cyclic shaped
o Hydrophobic groups that allows them to pass spontaneously through
bilayer
• E.g. Amyloid beta
o Main product of Alzheimer’s disease
o 39-42 amino acids
o Aß – formed after sequential cleavage of amyloid precursor protein
(APP) by the ß and y-secretases (autosomal-dominant mutation)
▪ APP: Transmembrane glycoprotein
Peptide Synthesis
• Peptides and proteins are present in every living cell and possess a variety of
biochemical activities: enzymes, hormones, antibiotics, toxins and receptors
• Important to study to understand the working of cell in health and disease →
potential in development of new therapeutics
Forming an Amid Bond
• Protein: amino acids joined together by amide bond
• An activated carbonyl will rapidly react with an amino (condensation reaction:
removal of water) → to form amide bond
• Need better leaving group than hydroxyl
