2.14 - Peptide and Protein Drugs: Issues and Solutions

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Polypeptides and proteins perform critical control and signaling functions in all tissues in the body and typically display high potency with low toxicity. However as candidate pharmaceuticals they have suffered from several limitations: short duration of action, limited receptor subtype selectivity, and low oral bioavailability. There are now general medicinal chemical and drug delivery approaches to answer each of these challenges. Truncation and modification lead to smaller agonists or antagonists. Duration of peptide action has been addressed with unnatural amino acid substitutions that alter physical properties to cause in vivo depoting effects, that block proteolysis or that rigidify the structure to address specificity issues. Modification by acylation, PEGylation, and protein conjugation prevent rapid clearance by glomerular filtration in the kidney. Modification of peptide/protein structural motifs brings these medicinal chemistry approaches into the protein realm. Drug delivery approaches have tremendous potential to add value, primarily through controlled-release injectable (to once yearly), intranasal, and inhalation routes of administration. Advances in protein and peptide manufacture, coupled with the completion of the Human Genome Project, mean that there is an abundance of feasible new targets. While peptidomimetic approaches are making tremendous strides, there remains a large and valuable role for modified peptide and protein pharmaceuticals in medicine. This chapter provides an overview of current, practical approaches to successful peptide pharmaceuticals.

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John J Nestor, Jr, PhD – CSO, Founding CEO; TheraPei Pharmaceuticals, Inc., has more than 25 years of pharmaceutical industry experience in drug discovery and scientific management, much of that time at the VP level in major pharma. He is co-inventor of 10 compounds selected for clinical development, including three that are now marketed drugs (Synarel, Antagon, Valcyte).

Prior to founding TheraPei Pharmaceuticals, John was Executive Vice President, Drug Discovery at Sequenom, leading the target validation and drug discovery groups. Prior to joining Sequenom, he served as President and Chief Scientific Officer at Consensus Pharmaceuticals. John was Vice President, Syntex Discovery Research and Director of the Institute of Bio-Organic Chemistry. Following the acquisition of Syntex by Roche, he served as Distinguished Scientist in the Roche Bioscience organization, until co-founding a chemistry-focused, drug discovery company, Helios Pharmaceuticals.

John obtained his BS in chemistry from the Polytechnic Institute of Brooklyn and a PhD in organic chemistry from the University of Arizona. After post-doctoral research at Cornell University with the Nobelist, Prof Vincent du Vigneaud, Dr Nestor joined Syntex Research to initiate peptide drug discovery. Dr Nestor is co-inventor of more than 40 issued US patents, author of more than 60 scientific articles, co-editor of 2 books. He also is an Associate Editor of the journal Letters in Drug Design and Discovery and on the Editorial Advisory Boards of Current Medicinal Chemistry and Medicinal Chemistry (Bentham Publishers).

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