Table Of ContentAAPS 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
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University of Strathclyde, Glasgow, UK
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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
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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 recep-
tors 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 reg-
ulations 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 pep-
tide drugs, and FDA’s Center for Drug Evaluation and Research (CDER) released a
draft guideline that specifically addresses peptide drugs. With this new develop-
ment, 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 pep-
tides. 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 therapeu-
tics. 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 jour-
nal 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
