Synthetic and Naturally Occurring Peptides Aspartame Artificial sweetener, dipeptide Glutathione Antioxidant present in body – thiol can be oxidized to disulfide sparing other biomolecules from oxidation Oxytocin (Petocin = name of drug) Peptide hormone that stimulates uterine contractions, lactation

Insulin is a Peptide Hormone that Stimulates Anabolic Processes Insulin stimulates the synthesis of energy storage molecules – glycogen, triglycerides, proteins.

Why Can’t Peptide and Protein Therapeutics Be Taken Orally? Monoclonal antibodies for cancer and inflamation: Trastuzamab (Herceptin) Infliximab (Remicade) Peptide hormones Insulin Human growth hormone (somatropin) Oxytocin Erythropoeitin (EPO) Peptide and proteins are not orally bioavailable Hydrolyzed in the GI tract (acidic stomach, proteases) Absorption issue with large molecules Intact peptides or proteins necessary for therapeutic effect

Chemical Synthesis of Peptides

Solid Phase Peptide Synthesis (SPPS) 1963 – Reported by Bruce Merrifield 1984 – Nobel prize awarded to Merrifield

Polystrene solid support Linker coupling reagent Fmoc Solid Phase Peptide Synthesis – Loading AA1 onto Resin

Fmoc Solid Phase Peptide Synthesis of Ala-Phe-Val Ala-Phe-Val

Fuzeon® is a 36 Amino Acid Peptide for HIV therapy One of the most complex drugs chemically synthesized on large scale Manufactured at Roche Pharmaceuticals Boulder, Colorado

Fuzeon® Interferes with HIV Entry Into T-Cells – Inhibits Fusion of Viral & Cellular Membranes Protease inhibitors Reverse transcriptase inhibitors Fusion inhibitor Fuzeon® binds to a glycopeptide on the HIV viral envelope and prevents T-cell entry Reduces HIV viral load and increases number of T-cells