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Peptide therapeutics are now becoming an innovative strategy for developing new medicines. During the past four-decades, the discovery and development of peptide therapeutics has grown exponentially, with more than a thousand peptide molecules currently being studied for therapeutic indications in a variety of disease areas, including metabolic diseases, infectious disease, cancer, and neurological disorders. Most of the clinical and commercial successes of peptide therapeutics have been seen in metabolic diseases and for peptide drugs acting on extracellular targets such as G protein-coupled receptors. Recently approved peptide-based drugs such as the glucagon-like peptide-1 agonists (Byetta™, Victoza™, Trulicity™ and Tanzeum™) for diabetes are great examples of clinical and commercial successes.

The use of peptide therapeutics directed at intracellular targets such as transcription factors, kinases and intracellular receptors, which could have utility in cancer and inflammatory diseases, has been somewhat limited. This is due not only to challenges in investigating intracellular targets, target effectiveness and validation, but also challenges in discovering and developing cell-penetrating peptides and understanding protein–protein interactions. Macrocyclic peptides have the ability to disrupt intracellular protein–protein interactions—targets often considered to be “undruggable”. The use of macrocyclic peptides opens up new opportunities to address a range of human diseases such as cancer and cardiovascular disease.

While much progress has been made in developing peptide therapeutics over the past several decades, we still need to better understand (1) the pharmaceutical properties required for drug-like peptides; (2) the correlation of nonclinical pharmacokinetics/pharmacodynamics that can translate to humans; (3) oral peptide delivery technologies; and (4) cost effectiveness of peptide drugs and their manufacture.

This book provides a holistic story from molecules to medicine, combining the themes of design, synthesis, biomarkers, and clinical applications of peptide-based therapeutics. Within each of these areas, authors cover essential background, key challenges, and strategies for overcoming these challenges. In some instances, authors share their views on the future of peptide therapies.

Reading Chapters 1 to 18 in succession will provide a comprehensive overview on peptide therapeutics. The extensive references covered in each chapter offer additional detail on the subject matter.

The first introductory chapter describes Renaissance in Peptide Drug Discovery: the Third Wave, highlighting a renaissance of peptide drug discovery relative to drug design, chemical space, cell permeability, and drug delivery to tackle intracellular protein–protein interaction targets.

The next chapters discuss the Identification and Validation of Peptide Therapeutic Targets and Indications—their discovery from knowledge of normal and pathologic physiology, biologic assays including cell-based molecular systems, and high-content in vivo screens; Peptide Biomarkers and Assay Development—including pre-clinical applications; and Peptide Library Technologies—screening and deconvolution of peptide libraries, including mathematical theory and computational analyses.

These are followed by chapters covering Peptide Lead Optimization—strategies and tactics for designing peptide analogs, with specific examples of peptide drug candidates, including clinical studies. For example, Macrocyclic Peptides for Intracellular Drug Targets discussed case studies in cyclic peptide cell permeability through active transport and transporter-mediated permeability; Structural Design for Bioactive Peptides covers metal-complexation and terminus- and side-chain modifications and cyclization; and ADME Properties of Peptide Therapeutics in Drug Discovery and Development explores understanding and integrating concepts of improving subcutaneous absorption, peptide elimination, identifying areas susceptible to metabolism in the lead-optimization process, and predicting human pharmacokinetics from nonclinical data.

Subsequent chapters focus on future therapeutic areas, illustrating peptide medicinal chemistry tools and techniques. For example, Designing an Effective Peptide Vaccine against viral disease, allergy and autoimmune disease, cancer immunotherapy; Peptide Therapeutics: Oncology; Development of Peptide-based Diagnostic and Therapeutic Agents in Oncology; Optimizing Peptides for Metabolic Diseases; Peptide Therapeutics: Neuropeptides; Developing Selective Nav1.7 Peptide Inhibitors for Pain; and Stress-responsive Peptides in Insects for wound healing and growth blocking.

Next are a set of future perspective chapters covering Technologies for Oral Delivery of Peptides—a comprehensive review of and strategies to increase paracellular or transcellular transport, and peptide molecules currently in pre-clinical or different stages of clinical development; Phylomer Libraries for peptide hits in phenotypic and target-directed screens; and the Solid-phase Peptide Synthesis, the State of the Art: Challenges and Opportunities, discussing green processes and integrated strategies.

The chapters are written by well-known key opinion leaders on the subject matter, from industry and academia all around the world. The goal of this book is to provide a valuable resource and reference, not only for the peptide researcher in the academic and pharmaceutical setting, but also for graduate students learning the discovery and development process as it relates to peptide-based medicines.

I would like to thank and express my gratitude to all the authors who have contributed to Peptide-based Drug Discovery: Challenges and New Therapeutics for their hard work in writing the chapters and sharing their expertise with a broad spectrum of readers. Thanks to the Royal Society of Chemistry project team leaders, especially Rowan Frame and Katie Morrey for their guidance and support. My special thanks to Professor David Rotella of Montclair State University for constantly encouraging me to put together this collection. I am grateful to Professor Richard DiMarchi, Linda & Jack Gill Chair in Biomolecular Sciences at Indiana University, and to Dr Michael Wagner, Head of Peptide Chemistry at Sanofi, Germany for writing a foreword and making recommendations for the book. I dedicate this book to my parents (Shravan and Kusum), and to my wife (Nisha) and children (Aaron and Nikita).

Ved Srivastava

Intarcia Therapeutics

Research Triangle Park, NC 27990, USA

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