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AAPS Advances in the Pharmaceutical Sciences Series 47 Seetharama D. Jois Editor Peptide Therapeutics Fundamentals of Design, Development, and Delivery AAPS Advances in the Pharmaceutical Sciences Series Volume 47 Series Editor Yvonne Perrie, Strathclyde Institute of Pharmacy and Biomedical Sciences University of Strathclyde, Glasgow, UK The AAPS Advances in the Pharmaceutical Sciences Series, published in partnership with the American Association of Pharmaceutical Scientists, is designed to deliver volumes authored by opinion leaders and authorities from around the globe, addressing innovations in drug research and development, and best practice for scientists and industry professionals in the pharma and biotech industries. Indexed in Reaxys SCOPUS Chemical Abstracts Service (CAS) SCImago EMBASE Seetharama D. Jois Editor Peptide Therapeutics Fundamentals of Design, Development, and Delivery Editor Seetharama D. Jois School of Basic Pharmaceutical and Toxicological Sciences University of Louisiana at Monroe, College of Pharmacy Monroe, LA, USA Editorial contact Carolyn Spence ISSN 2210-7371 ISSN 2210-738X (electronic) AAPS Advances in the Pharmaceutical Sciences Series ISBN 978-3-031-04543-1 ISBN 978-3-031-04544-8 (eBook) https://doi.org/10.1007/978-3-031-04544-8 © American Association of Pharmaceutical Scientists 2022 Dual Imprint with AAPS Springer This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. 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This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland Preface It is estimated that by 2024, the projected market for peptide therapeutics will be around $50 billion. Thus, a book that explains with fundamental principles how the peptide-based drugs are designed and what are the steps needed to develop a peptide- based therapeutic is essential. Peptides are natural ligands for many receptors in the human body, and many, such as hormones, neurotransmitters, and growth factors, have physiological roles. Historically, peptide drugs were originated from naturally occurring ligand peptides that were modified for therapeutic purposes. However, advances in synthetic chemistry of peptides, more available raw material for synthesis, and efficiency of peptide synthesis on an industrial scale have made the synthetic peptide market successful. At present, peptide-based therapeutics are in demand in two main areas: metabolic diseases and oncology. More than 80 peptide- based drugs approved by the FDA are now on the market, and more than 150 types of therapeutic peptides are in the pre-clinical stage. The book covers the design concept of peptide therapeutics from fundamental principles using structural biology and computational approaches. The chapters are arranged in a linear fashion. A fresh science graduate or a scientist who works on small molecules can follow the design and development of peptide therapeutic to understand the basic concepts. Each chapter is written by experts from academia as well as industry. Rather than covering extensive literature, first few chapters of the book provide fundamental concepts of design, synthesis, and computational aspects of peptide therapeutics. Chapters on peptide delivery and stability cover basic as well as recent literature applicable to peptide drugs. In terms of regulations to approve the peptide drugs for therapeutic purposes, there were no special FDA regulations a decade ago. Larger peptides were treated as proteins, and smaller peptides were treated as small molecules. In 2013, the United States Pharmacopeial Convention (USP) formed a therapeutic peptide expert panel for guidance on peptide drugs, and FDA’s Center for Drug Evaluation and Research (CDER) released a draft guideline that specifically addresses peptide drugs. With this new development, there are guidelines for peptide therapeutics to bring it to the market. The last chapter covers regulatory issues related to peptide therapeutics and some new devel- opments in FDA regarding peptide drugs. The examples provided in the chapters v vi Preface can be used to perform peptide formulation considerations for the designed peptides. Some chapters are written as a combination of basic principles and protocol so that scientists can adopt these methods to their research work. The book has nine chapters, and each chapter can be read as an independent chapter on a particular concept. The book can be used as a reference for a pharmaceutical or biomedical scientists or graduate students who want to pursue their career in peptide therapeutics. Most of the academic labs work with the design, synthesis, and structure- activity relationship of peptides. These scientists collaborate with drug delivery scientists to propose peptide delivery. However, this book comprehensively pro- vides all the concepts for a reader. The editor would like to thank the contributors as well as reviewers for their time and effort. The editor would also like to thank Mr. Prajesh Shrestha, a graduate student in the School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, for helping with final editing and formatting. Monroe, LA, USA Seetharama D. Jois Contents 1 Basic Concepts of Design of Peptide-Based Therapeutics . . . . . . . . . . 1 Seetharama D. Jois 2 Peptide Synthesis: Methods and Protocols . . . . . . . . . . . . . . . . . . . . . . 51 Ted Gauthier and Dong Liu 3 Computational Methods for Peptide Macrocycle Drug Design . . . . . 79 Vikram Khipple Mulligan 4 Strategies to Optimize Peptide Stability and Prolong Half-Life . . . . . 163 Sophia M. Shi and Li Di 5 Therapeutic Peptide Delivery: Fundamentals, Formulations, and Recent Advances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183 Deepal Vora, Amruta A. Dandekar, and Ajay K. Banga 6 Liposome Nanocarriers for Peptide Drug Delivery . . . . . . . . . . . . . . . 203 Jafrin Jobayer Sonju, Achyut Dahal, and Seetharama D. Jois 7 Peptides and Their Delivery to the Brain . . . . . . . . . . . . . . . . . . . . . . . 237 Waleed Elballa, Kelly Schwinghamer, Eric Ebert, and Teruna J. Siahaan 8 Emerging Peptide Drug Modalities for Intracellular Target Space . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 267 Tomi K. Sawyer 9 Regulatory Issues for Peptide Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . 287 Seetharama D. Jois Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307 vii About the Author Seetharama D. Jois is a Professor of Medicinal Chemistry in the School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, USA. Before joining the University of Louisiana at Monroe in 2006, he worked as an assistant professor in the Department of Pharmacy at the National University of Singapore for 6 years. Dr. Jois obtained his PhD degree in 1994 from the Molecular Biophysics Unit, Indian Institute of Science (IISc), Bangalore, India, and a master’s degree in physics from the University of Mysore, India. After his PhD degree, Dr. Jois obtained extensive training in pharmaceutical chemistry research at the University of Kansas in Lawrence, KS. During the past 20 years, he has established research in a unique area of drug design discovery, namely protein-protein interaction and drug design. He has secured funding from NIH and state agencies for his research. Dr. Jois has published more than 100 publications and has 3 US patent applications. Dr. Jois has edited a book Drug Design and Discovery: Methods and Protocols (Humana Press 2011) and special issues of journal series including Current Pharmaceutical Design, “Adhesion Molecules and Drug Targeting” (2006, Bentham Science Publisher LTD); and Current Pharmaceutical Design, “Biomaterial” (2008 Bentham Science Publisher LTD). He has 20 years of teaching experience in pharmacy schools and has published his innovative method of teaching in the American Journal of Pharmacy Education (2010, 74(8): 147). ix Chapter 1 Basic Concepts of Design of Peptide-Based Therapeutics Seetharama D. Jois Contents 1.1 Introduction 2 1.2 Three-Dimensional Structure of Peptides 3 1.3 Targeting a Biochemical Pathway 5 1.4 Designing Drug When the Target Receptor Structure Is Known 6 1.4.1 The Binding Site and 3D Structure of Receptor Cavity/Surface 6 1.4.2 Agonist or Antagonist? 6 1.4.3 Pharmacophore Identification 7 1.5 Peptidomimetic 12 1.5.1 Backbone or Side-Chain Modification 12 1.5.2 Secondary Structure Mimics 14 1.6 Protein-Protein Interaction and Peptide Drug Design 14 1.7 Peptides from Natural Sources and Modification for Drug Design 16 1.8 Screening Assays 17 1.9 Binding Assays 17 1.10 Examples of Peptide-Based Drug Design 18 1.10.1 Enzyme-Based Drug Design 18 1.10.2 Receptor Ligand-Based Drug Design 22 1.10.3 Example of a Peptide from Natural Resources: Polymyxin B 28 1.10.4 Protein-Protein Interaction and Drug Design 32 1.11 Summary 41 References 41 Abstract Peptides are natural ligands for numerous receptors in the human body, and many of these, such as hormones, neurotransmitters, and growth factors, have physiological roles. Peptides are highly selective and relatively well tolerated in the human body. More than 80 peptide-based drugs approved by the FDA are now on the market. A major challenge in peptide-based therapeutics is in vivo stability of peptides for oral administration. There have been several attempts to increase the S. D. Jois (*) School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, LA, USA e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Switzerland AG 2022 1 S. D. Jois (ed.), Peptide Therapeutics, AAPS Advances in the Pharmaceutical Sciences Series 47, https://doi.org/10.1007/978-3-031-04544-8_1