Peptide-based Drug Discovery

Challenges and New Therapeutics

Ved Srivastava, Ved Srivastava

• Publisher: Royal Society of Chemistry
• Year: 2017
• ISBN:
  9781788011716
• Edition: 1
• Topic: Biological Sciences
• Subtopic: Biochemistry
• Index: Biological Sciences

With potentially high specificity and low toxicity, biologicals offer promising alternatives to small-molecule drugs. Peptide therapeutics have again become the focus of innovative drug development efforts backed up by a resurgence of venture funds and small biotechnology companies.

What does it take to develop a peptide-based medicine? What are the key challenges and how are they overcome? What are emerging therapeutics for peptide modalities? This book answers these questions with a holistic story from molecules to medicine, combining the themes of design, synthesis and clinical applications of peptide-based therapeutics and biomarkers. Chapters are written and edited by leaders in the field from industry and academia and they cover the pharmacokinetics of peptide therapeutics, attributes necessary for commercially successful metabolic peptides, medicinal chemistry strategies for the design of peptidase-resistant peptide analogues, disease classes for which peptide therapeutic are most relevant, and regulatory issues and guidelines.

The critical themes covered provide essential background information on what it takes to develop peptide-based medicine from a chemistry perspective and views on the future of peptide drugs. This book will be a valuable resource not only as a reference book for the researcher engaged in academic and pharmaceutical setting, from basic research to manufacturing and from organic chemistry to biotechnology, but also a valuable resource to graduate students to understand discovery and development process for peptide-based medicine.

Foreword 1

As a class, macromolecules include numerous medicinal agents with high specificity, low off-target toxicity and, most importantly, unique efficacy. Peptide therapeutics represent a subsection of this broader class and include a number of indispensable life-saving medicines, with none more notable than insulin. The application of modern synthetic and analytical technology to peptides has generated a resurgence of interest in academic and commercial laboratories dedicated to the discovery and development of novel peptide-based medicines. What does it take to develop a peptide-based medicine? What are the key challenges and how are they being addressed? In which traditional therapeutic areas have peptides been most successful and in which new fields are they likely to be employed in the future? This collection of state-of-the-art reports addresses these and related questions in a holistic manner. It presents the evolution of a chemical entity to a registered medicine, presenting the seminal themes of design, synthesis, biological assessment and clinical development with associated biomarkers. This text summarizes a wealth of recent and current research projects that exemplify the attributes associated with successful research and development. Each chapter is authored by an internationally recognized opinion leader representing a cross-section of commercial and academic laboratories. The book will serve as a valuable reference volume for experienced peptide scientists, as well as an educational resource for younger scientists in training. I recommend it as a significant contribution that highlights current themes in the discovery and development of peptide-based medicine.

Richard DiMarchi

Indiana University

Foreword 2

Since the discovery of therapeutically important hormones such as insulin and oxytocin, peptide-based drug discovery has gained significant importance. In addition to demonstrating their utility as therapeutic agents, peptides are finding increased use as molecular probes to understand biological pathways of human disease and as diagnostic tools.

As a therapeutic modality, peptides address an important gap between classical small-molecule drugs and antibodies with a rather high molecular weight. The latter agents are typically administered via intravenous or subcutaneous routes. The significant success of peptides in biomedicine has become possible as a result of the remarkable progress that has been made with respect to peptide design, manufacturing, improved stability, half-life prolongation and new delivery systems. Nowadays, peptides can be designed to address targets in the intracellular space, and research into the oral delivery of peptides is making significant progress.

Currently, more than 60 peptidic drugs are approved as marketed medicines and more than 350 peptide therapeutics are under clinical investigation targeting a wide variety of disease indications; oncology and metabolic disorders, but also neurological and inflammatory disorders. Remarkably, the current scope of peptide drugs is not limited to injectables, since alternative formulations and needle-free systems allowing for pulmonary, transdermal and oral delivery have either advanced to the market or are in late-stage clinical studies. Although the United States and Europe have so far been the key markets for therapeutic peptides, Asia Pacific and Latin America will offer significant opportunities in the coming years.

Today, peptide-based drug discovery is undertaken in a large number of laboratories across the world, including in large pharmaceutical companies and biotech and academic institutions. In fact, the enormous progress and opportunities in peptide therapeutics outlined above have led to the launching of several peptide-focused new companies in Europe, the US and Asia over the past decade—biotech or contract research or manufacturing organizations. This book attests to a promising future for the field of peptide science, which could further broaden in scope and offer new opportunities and therapeutic applications.

In Peptide-based Drug Discovery, well recognized experts in the field share their insight and views on many of these aspects. Central topics include the early identification of lead structures, design considerations and peptide optimization strategies with the overall goal to develop next-generation peptides as effective drugs for a variety of indications, as well as diagnostic tools and biomarkers.

I strongly applaud and recommend this book; it will serve as a valuable source of knowledge for experienced peptide and protein scientists in industry and academia, and also for the many young scientists aspiring to enter this field of research.

Michael Wagner

Sanofi-Aventis Deutschland GmbH

Frankfurt, Germany

Preface

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 Na_v1.7 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

Biography

Dr Ved Srivastava is Vice President of Peptide Chemistry at Intarcia Therapeutics. Prior to that he co-founded and was Vice President of Chemistry at Phoundry Pharmaceuticals, a peptide therapeutic discovery company that was acquired by Intarcia. Prior to Phoundry, he was the Head of Peptide Chemistry at GlaxoSmithKline. Ved spent several years in a leadership role with Amylin Pharmaceuticals, where he focused on the discovery and development of novel peptide hormones for diabetes, obesity and neuropsychiatric therapies. He has participated in the development and commercialization of Symlin™, Byetta™ and Bydureon™, first-in-class medicines for the treatment of diabetes.

Ved has more than 25 years of experience with expertise in drug discovery and development in the area of metabolic diseases, the central nervous system and inflammation, with major emphasis in peptide medicinal chemistry, chemistry manufacturing and control and peptide drug delivery. He has numerous scientific disclosures, including patents, scientific articles and invited lectures.

Ved is the editor of two other books, Peptide 2015 (American Peptide Society) and Comprehensive Medicinal Chemistry III, Volume 7. Biologics Medicine (Elsevier). He is an editorial board member of The FASEB Journal (the Federation of American Societies for Experimental Biology); and an editorial advisory board member of the Current Protein & Peptide Science journal.

Ved serves in the governance and leadership team of the American Peptide Society and the American Chemical Society and other peptide societies. Ved is also an appointed member of the BIO1 Peptides and Insulins Expert Committee and the Therapeutic Peptides Expert Panel of the US Pharmacopeial Convention in partnership with the US Food and Drug Administration. He earned a PhD in organic chemistry from the University of Lucknow, India, and had subsequent postdoctoral appointments at the University of Georgia and the University of Colorado School of Medicine.

Ved Srivastava

Intarcia Therapeutics, NC, USA