Peptide and Peptidomimetic Therapeutics: From Bench to Bedside

Front Cover
Peptide and Peptidomimetic Therapeutics
Copyright Page
Contents
List of contributors
Preface
	References
1 History
	1 Therapeutic peptides: historical perspectives and current development trends
		1.1 Introduction: The evolution of peptide therapeutics
			1.1.1 Moving beyond native peptides
			1.1.2 Nonpeptide alternatives to peptide therapeutics
			1.1.3 Current state of peptide therapeutics discovery
		1.2 The therapeutic peptides dataset
			1.2.1 Development status of therapeutic peptides
			1.2.2 Physical characteristics of therapeutic peptides
				1.2.2.1 Peptide length
				1.2.2.2 Chemical basis of peptide therapeutics
				1.2.2.3 The rise of peptide conjugates
				1.2.2.4 Intrinsic peptide stability: primary sequence and higher-order structural protection
			1.2.3 Molecular targets of therapeutic peptides
			1.2.4 Approvals and uses of therapeutic peptides
		1.3 Clinical development timelines and benchmarks for peptides
		1.4 The future of peptide therapeutics
		Acknowledgments
		References
2 Basic science
	2 Therapeutic peptidomimetics: targeting the undruggable space
		2.1 Introduction
		2.2 The “undruggable” space
		2.3 Therapeutic peptidomimetics
		2.4 Examples of therapeutic peptidomimetics based on applications
			2.4.1 Antimicrobial peptidomimetics
			2.4.2 Anticancer peptidomimetics
			2.4.3 Immunodetection peptidomimetics
		2.5 Conclusion
		References
	3 Tailoring peptides and peptidomimetics for targeting protein–protein interactions
		3.1 Introduction
		3.2 Helix mimetics
		3.3 Extended structures
		3.4 Loops
		3.5 Summary
		Acknowledgments
		References
	4 Advances in peptide synthesis
		4.1 Introduction to peptides
		4.2 Fluorenylmethyloxycarbonyl solid-phase peptide synthesis
			4.2.1 Three major developments
			4.2.2 Extensions of solid-phase peptide synthesis
		4.3 Approaches for accelerated peptide synthesis
			4.3.1 Microwave-assisted peptide synthesis
			4.3.2 Flow reactor and peptide reactor
		4.4 Advances in chemical synthesis of several important classes of peptides
			4.4.1 Difficult sequences
			4.4.2 Transmembrane peptides
			4.4.3 Cyclic peptides
		4.5 Conclusions and outlook
		Acknowledgments
		References
	5 Stapled peptidomimetic therapeutics
		5.1 Introduction
		5.2 Development of stapled peptide inhibitors of eukaryotic initiation factor 4E
			5.2.1 Eukaryotic initiation factor 4E in translation initiation, regulation and oncogenesis
			5.2.2 Design of Stapled peptide inhibitors of eukaryotic initiation factor 4E
		5.3 Development of all d-amino acid stapled peptides
			5.3.1 Design of all D-stapled peptide inhibitors of Mdm2
			5.3.2 Development of double stapled and stitched peptides
		5.4 Development of nonhelical stapled peptides
		5.5 Stapling modulates membrane permeability and aggregation propensity of peptide therapeutics
			5.5.1 Stapling modulates peptide membrane permeability
			5.5.2 Stapling affects peptide aggregation propensity
		5.6 Concluding remarks
		Acknowledgments
		References
	6 Ring-closing metathesis/transannular cyclization to azabicyclo[X.Y.0]alkanone dipeptide turn mimics for biomedical applic...
		6.1 Introduction
		6.2 Ring-closing metathesis/transannular cyclization approach for making bicycles with different ring size
			6.2.1 ω-Olefin amino acid synthesis
			6.2.2 Dipeptide formation and ring-closing metathesis
			6.2.3 Transannular cyclization
		6.3 Installation of ring substituents to mimic side chains
			6.3.1 Nucleophilic substitution
			6.3.2 Adding side-chain functionality by elimination
			6.3.3 Synthesis and application of substituted ω-olefin amino acids
		6.4 Conformational analysis of unsaturated lactam and azabicyclo[X.Y.0]alkanone amino esters by X-ray crystallography illus...
			6.4.1 Crystal structures of 7–10-member unsaturated lactams
			6.4.2 Crystal structures of azabicyclo[X.Y.0]alkanones
		6.5 Biomedical application of azabicyclo[X.Y.0]alkanone dipeptide mimics as prostaglandin F2α receptor modulators to delay ...
			6.5.1 Targeting the prostaglandin F2α receptor
			6.5.2 From peptide to azabicyclo[X.Y.0]alkanone mimetics that delay labor in mice
		6.6 Conclusion
		Acknowledgments
		References
3 Drug discovery
	7 The current state of backbone cyclic peptidomimetics and their application to drug discovery
		7.1 Introduction
		7.2 Peptide synthesis and backbone cyclization
		7.3 Backbone cyclic peptides mimicking natural peptides
			7.3.1 Neuropeptide family
				7.3.1.1 Substance P
				7.3.1.2 Pheromone biosynthesis activating neuropeptide
				7.3.1.3 Bradykinin
			7.3.2 Peptide hormones
				7.3.2.1 Somatostatin
				7.3.2.2 Gonadotropin-releasing hormone
				7.3.2.3 Alpha-melanocyte-stimulating hormone
			7.3.3 Protein mimetics
				7.3.3.1 Insulin-like growth factor I receptor
				7.3.3.2 Bovine pancreatic trypsin inhibitor
				7.3.3.3 Human immunodeficiency virus
				7.3.3.4 Leishmania’s receptor for activated C-kinase
				7.3.3.5 Protein kinase B (PKB, or Akt)
				7.3.3.6 Nuclear factor-kappa B (NF-κB)
				7.3.3.7 Human leukocyte antigen class II histocompatibility, D related beta chain (HLA-DRB1)
				7.3.3.8 Chemokine (C-C motif) receptor 2 (CCR2)
				7.3.3.9 Src homology region 2 domain-containing phosphatase-1 (SHP-1)
		7.4 The future of backbone cyclic peptidomimetics
		References
	8 Pharmacokinetics and pharmacodynamics of peptidomimetics
		8.1 Introduction
		8.2 Pharmacokinetics of peptidomimetics
		8.3 Absorption
		8.4 Distribution
		8.5 Metabolism
		8.6 Excretion
		8.7 Pharmacodynamics of peptidomimetics
		8.8 Current perspectives
		8.9 Conclusions
		Acknowledgments
		References
	9 Formulation of peptides and peptidomimetics
		9.1 Introduction
		9.2 Challenges in formulating peptides
			9.2.1 Chemical instability
			9.2.2 Stereoisomerism
			9.2.3 Self-association
			9.2.4 Physical instability
		9.3 Formulation approaches for peptides
			9.3.1 Chemical modifications
			9.3.2 Polyethylene glycosylation
			9.3.3 Glycosylation
			9.3.4 Mannosylation
			9.3.5 Enzyme inhibitors
			9.3.6 Penetration enhancers
			9.3.7 Colloidal systems
				9.3.7.1 Liposomes
				9.3.7.2 Micro- and nanoparticles
				9.3.7.3 Reverse micelles
				9.3.7.4 Emulsions
				9.3.7.5 Mucoadhesive polymeric system
			9.3.8 General excipients
				9.3.8.1 Buffer systems
				9.3.8.2 Solvent system
				9.3.8.3 Preservatives
				9.3.8.4 Stabilizers
		9.4 Formulation strategies for peptidomimetics
			9.4.1 Prodrug approach
			9.4.2 Addition of unnatural amino acids
			9.4.3 Inversion of chirality
			9.4.4 Backbone cyclization
		9.5 Future directions and conclusions
		Acknowledgments
		References
	10 Medical use of cell-penetrating peptides: how far have they come?
		10.1 Introduction
			10.1.1 Cell-penetrating peptide structure and mechanism at a glance
				10.1.1.1 Cell-penetrating peptide classification
				10.1.1.2 Mechanisms of cellular entry
		10.2 Application of cell-penetrating peptides in biomedicine
			10.2.1 Methods of cell-penetrating peptide-cargo construct formation
				10.2.1.1 Covalent cell-penetrating peptide-cargo conjugates
				10.2.1.2 Noncovalent cell-penetrating peptide-cargo complexes
			10.2.2 Medical fields with cell-penetrating peptide applications
		10.3 How to improve cell-penetrating peptide-based applications
			10.3.1 Improving proteolytic resistance of cell-penetrating peptides
			10.3.2 Improving cytosolic accumulation of cell-penetrating peptides
			10.3.3 Improving cell selectivity and intracellular targeting of cell-penetrating peptides
		10.4 Cell-penetrating peptides in preclinical studies
			10.4.1 Cell-penetrating peptides in vaccination
			10.4.2 Cell-penetrating peptide-based strategies in cognitive dysfunction
			10.4.3 Cell-penetrating peptides in CRISPR/Cas9 development
			10.4.4 Other companies developing cell-penetrating peptide-based drugs in preclinical trials
		10.5 Cell-penetrating peptides in clinical studies
			10.5.1 Duchenne’s muscular dystrophy
			10.5.2 Cancer indications
			10.5.3 Neurological indications
		10.6 Concluding remarks
		References
	11 Intracellular peptides as drug prototypes
		11.1 Introduction
		11.2 Evidence that intracellular peptides come from proteasomal protein degradation
		11.3 Experimental data on the biological significance of intracellular peptides
		11.4 Evidence for biological significance of intracellular peptides in the central nervous system
		11.5 Intracellular peptides profiles dramatically change in neurodegenerative diseases
		11.6 Intracellular peptides disruption in anterior temporal lobe and corpus callosum of postmortem schizophrenic brains
		11.7 Intracellular peptides as tools for therapeutic development
		11.8 Concluding remarks
		Funding
		References
	12 Applications of computational three-dimensional structure prediction for antimicrobial peptides
		12.1 Introduction
		12.2 What is a protein three-dimensional model?
		12.3 Comparative modeling
		12.4 Ab initio modeling
		12.5 Contact-assisted modeling
		12.6 Conclusions
		Acknowledgments
		References
4 Therapeutic applications
	13 Knottin peptidomimetics as therapeutics
		13.1 Historical context
		13.2 Why “knottin”?
		13.3 The highly conserved basic structural cystine-stabilized beta-sheet motif
		13.4 Knottins for drug design and engineering
			13.4.1 Very diverse functions and sequences
			13.4.2 Stable structures accessible to chemical synthesis
			13.4.3 Knottin-based therapies
		13.5 Summary
		References
	14 Venom peptides and peptidomimetics as therapeutics
		14.1 Introduction
		14.2 Peptide categories
			14.2.1 Natural
			14.2.2 Synthetic
		14.3 ATP synthase as a potent molecular drug target
		14.4 Peptides as selective inhibitors of ATP synthase
		14.5 Conclusion
		References
		Further reading
	15 Therapeutic peptides targeting protein kinase: progress, challenges, and future directions, featuring cancer and cardiov...
		15.1 Introduction
		15.2 Protein kinase architecture
			15.2.1 Protein kinase catalytic domains
		15.3 Kinase inhibitors
			15.3.1 Small molecules targeting protein kinases
			15.3.2 Antibodies targeting protein kinases
		15.4 Peptides targeting protein kinases
			15.4.1 Peptide-based kinase inhibitors targeting kinase-substrate sites
				15.4.1.1 Peptide-based kinase inhibitors targeting pseudosubstrate sites
					15.4.1.1.1 Peptides as substrate-based inhibitors of protein kinases in cardiovascular disease
					15.4.1.1.2 Peptides as substrate-based inhibitors of protein kinases in cancer
			15.4.2 Peptide-based kinase inhibitors targeting docking sites
				15.4.2.1 Peptide-based kinase inhibitors targeting docking sites in cardiovascular disease
				15.4.2.2 Peptide-based kinase inhibitors targeting docking sites in cancer
				15.4.2.3 Peptide-based kinase inhibitors targeting anchoring proteins
				15.4.2.4 Peptide-based kinase inhibitors targeting anchoring proteins in cardiovascular disease
				15.4.2.5 Peptide-based kinase inhibitors targeting anchoring proteins in cancer
			15.4.3 Additional approaches to develop peptide-based kinase inhibitors
				15.4.3.1 Development of protein kinase inhibitors using bioinformatics and structural data
				15.4.3.2 Bisubstrate and bivalent approaches
		15.5 Conclusions and perspectives
		Funding
		References
	16 Therapeutic peptidomimetics for infectious diseases
		16.1 Introduction
		16.2 Emerging peptidomimetic technologies
			16.2.1 Antibody mimetics
			16.2.2 Tripeptide analogs
			16.2.3 Cyclic heptapseudopeptides
		16.3 Peptidomimetics in the therapy of infectious diseases
			16.3.1 Plasmepsin inhibitors with potent antimalarial activity
			16.3.2 Application of peptidomimetics for targeting multidrug-resistant organisms
			16.3.3 Antiinflammatory peptidomimetics
			16.3.4 Peptidomimetics targeting oral bacteria
			16.3.5 Application of peptidomimetics in microbial vaginosis
			16.3.6 Application of peptidomimetics to diphtheria toxin
		16.4 Peptidomimetics in vaccine design
		16.5 Peptidomimetics in diagnosis of infectious disease
		16.6 Future prospects of peptidomimetics in infectious diseases
		References
	17 Antiparasitic therapeutic peptidomimetics
		17.1 Introduction to parasites
		17.2 Kinetoplastida parasites
		17.3 Human African trypanosomiasis
		17.4 Chagas disease
		17.5 Leishmaniasis
		17.6 Peptides as drug candidates
		17.7 Antimicrobial peptides
			17.7.1 Defensins
			17.7.2 Temporins
			17.7.3 Cathelicidins
			17.7.4 Melittin
			17.7.5 Dermaseptins
			17.7.6 Bacteriocins
			17.7.7 Histatins
			17.7.8 Combination therapy of antimicrobial peptides
		17.8 Marine peptides
		17.9 Peptides targeting vital proteins and their interactions
			17.9.1 Glycoprotein gp63
			17.9.2 Leishmania receptor for activated C-kinase and Trypanosoma receptor for activated C-kinase
			17.9.3 Gp85-cytokeratin interaction
			17.9.4 N-mirystoyltransferase enzyme
			17.9.5 Breast cancer 2
			17.9.6 Pseudomonas exotoxin
		17.10 Peptides that target critical pathways
			17.10.1 Endoplasmic reticulum-associated degradation pathway
			17.10.2 Glycolysis pathway
		17.11 Peptides that target proteases
			17.11.1 Cysteine peptidase B
		17.12 Dipeptides
		17.13 Peptoids
		17.14 Peptides as drug delivery agents
		17.15 From antibody to peptides
		17.16 Peptides as diagnostic tools for parasitic diseases
		17.17 Concluding remarks
		References
	18 Peptides and antibiotic resistance
		18.1 Introduction
		18.2 Classification of antimicrobial peptides
			18.2.1 Size
			18.2.2 Conformation
			18.2.3 Charge
			18.2.4 Amphipathicity
			18.2.5 Polar angle
			18.2.6 Hydrophobicity
		18.3 Antimicrobial peptide mechanisms of action
		18.4 Advantages of antimicrobial peptides compared to conventional antibiotics
		18.5 Mechanisms of bacterial resistance to antimicrobial peptides
			18.5.1 Proteolysis
			18.5.2 Capsular polysaccharides
			18.5.3 Cell wall
			18.5.4 Plasma membrane
			18.5.5 Efflux pumps
			18.5.6 Biofilm formation
		18.6 Approaches for overcoming bacterial resistance to antimicrobial peptides
		18.7 Conclusion
		References
	19 Antimicrobial peptides and the skin and gut microbiomes
		19.1 Introduction
		19.2 Mechanism of action
			19.2.1 Alpha helices
			19.2.2 Beta sheets
			19.2.3 Antimicrobial proteins
		19.3 Regulation of antimicrobial peptides
			19.3.1 Regulation of cathelicidins
			19.3.2 Regulation of dermcidin
			19.3.3 Regulation of β-defensins
		19.4 Antimicrobial peptides in the skin
			19.4.1 Overall function of antimicrobial peptides in the skin
			19.4.2 Antimicrobial proteins and skin microbiota
			19.4.3 Environmental effects on skin antimicrobial peptides
			19.4.4 Antimicrobial peptides in skin disorders
			19.4.5 Antimicrobial peptides in regulation of epithelial damage
			19.4.6 Emerging skin antimicrobial proteins
		19.5 Antimicrobial peptides in the intestine
			19.5.1 α-Defensins in the intestine
			19.5.2 β-Defensins in the intestine
			19.5.3 Cathelicidins in the intestine
			19.5.4 Antimicrobial peptides and the intestinal microbiome
			19.5.5 Antimicrobial peptides in inflammatory bowel diseases
		19.6 Therapeutic opportunities
		References
	20 Peptide and peptidomimetic-based vaccines
		20.1 Vaccines
		20.2 Vaccine formats
			20.2.1 Live attenuated vaccines
			20.2.2 Inactivated vaccines
			20.2.3 Subunit vaccines
				20.2.3.1 Protein
				20.2.3.2 Polysaccharide
				20.2.3.3 Conjugate
			20.2.4 Toxoid vaccines
		20.3 Peptides or peptidomimetics as potential immunogens
		20.4 Peptide-based vaccines
			20.4.1 Epitope selection
			20.4.2 Characterization of epitopes
			20.4.3 Immunostimulants and vaccine delivery
				20.4.3.1 Immunostimulants
				20.4.3.2 Delivery system
					20.4.3.2.1 Route of administration
		20.5 Advantages of peptide and peptidomimetic vaccines
		20.6 Current and future perspectives
		References
	21 Therapeutic peptidomimetics for cancer treatment
		21.1 Introduction
		21.2 Peptidomimetics targeting proteasomal protein regulation
			21.2.1 The role of the ubiquitin–proteasome system in cancer
			21.2.2 Anticancer peptidomimetics targeting the ubiquitin–proteasome system
		21.3 Peptidomimetic matrix metalloproteinase inhibitors
		21.4 Aminopeptidase inhibitors
			21.4.1 Aminopeptidase N structure and functions
			21.4.2 Aminopeptidase N inhibitors
		21.5 Peptidomimetics acting on the Ras-Raf-MAPK pathway
			21.5.1 The Ras-Raf-MAPK pathway
			21.5.2 Direct Ras inhibitors
			21.5.3 Indirect Ras inhibitors: peptidomimetic inhibitors of Ras processing by farnesyltranferase
		21.6 Anticancer peptidomimetics targeting HER2, HER2-HER3, and HER2-VEGF
			21.6.1 HER2 as an anticancer target
			21.6.2 Peptidomimetic inhibitors of HER2-EGFR and HER2-HER3 heterodimerization
		21.7 Inhibitors of insulin-like growth factor-1 receptors
			21.7.1 Insulin-like growth factor-1 receptors
			21.7.2 Anti-IGF1R peptidomimetics
		21.8 Peptidomimetic integrin inhibitors
		21.9 Peptidomimetics acting on transcriptional regulation
			21.9.1 Peptidomimetics acting on the signal transducer and activator of transcription pathway
			21.9.2 Peptidomimetics acting at the Notch, TGFβ, and β-catenin pathways
		21.10 Anticancer peptidomimetics that modulate hormone action
		21.11 Peptidomimetics targeting regulation of apoptosis
		21.12 Peptidomimetics targeting tubulin
		21.13 Conclusion
		References
	22 Immunomodulatory peptidomimetics for multiple sclerosis therapy—the story of glatiramer acetate (Copaxone)
		22.1 Introduction
		22.2 Peptidomimetics for modulation of experimental autoimmune encephalomyelitis / multiple sclerosis
			22.2.1 Antigen-specific approaches
		22.3 Approaches for blocking activation signals
		22.4 The story of glatiramer acetate (Copaxone)
		22.5 Immunomodulatory mechanisms
		22.6 Neuroprotective repair mechanisms
		22.7 Concluding remarks
		References
	23 Therapeutic peptidomimetics in metabolic diseases
		23.1 Introduction
		23.2 Key regulators of glucose homeostasis
			23.2.1 Insulin
			23.2.2 The glucagon gene and its products
				23.2.2.1 Glucagon
				23.2.2.2 GLP-1 and GLP-2
				23.2.2.3 Glicentin and oxyntomodulin
		23.3 The cephalic phase
			23.3.1 Cephalic phase insulin release
		23.4 The incretin effect, the duodenum, and the small intestine
			23.4.1 Glucose-dependent insulinotropic polypeptide, or gastric inhibitory polypeptide (GIP)
			23.4.2 GLP-1
			23.4.3 DPP-4
			23.4.4 Sodium-glucose cotransporter 1
		23.5 Transport from the bloodstream into tissues
		23.6 Reaching the endocrine pancreas
		23.7 Target tissues, bioconversion, and storage
			23.7.1 Liver
			23.7.2 Adipose tissues
		23.8 Secretion in the kidney
		23.9 Diabetes
		23.10 Insulin and insulin mimetics
			23.10.1 Mammalian insulin
			23.10.2 Recombinant human insulin
			23.10.3 Synthetic insulin
			23.10.4 Short-acting and long-acting insulin as drugs
		23.11 Synthetic control of blood glucose levels
			23.11.1 GLP-1 analogs
			23.11.2 SGLT2 inhibitors reduce hyperglycemia and treat several types of kidney disease
		23.12 Summary
		References
	24 Peptide therapeutics in anesthesiology
		24.1 Introduction
		24.2 Peptide use in anesthesiology practice
			24.2.1 Insulin
			24.2.2 Protamine
			24.2.3 Bivalirudin and desirudin
			24.2.4 Vasopressin
			24.2.5 Desmopressin
			24.2.6 Octreotide
			24.2.7 Oxytocin
			24.2.8 Eptifibatide
			24.2.9 Secretin
			24.2.10 Nesiritide
			24.2.11 Cyclosporine
			24.2.12 Ziconotide
			24.2.13 Ecallantide
		24.3 Peptide-like agents
			24.3.1 Amino acid analogs, aminocaproic acid and tranexamic acid
			24.3.2 Peptide-like drugs
		24.4 Properties to consider when administering peptides
		24.5 Summary and future directions
		Acknowledgments
		References
	25 Cardiovascular-derived therapeutic peptidomimetics in cardiovascular disease
		25.1 Introduction
		25.2 Adrenomedullin
			25.2.1 Background
			25.2.2 Genetics and translation
			25.2.3 Distribution
			25.2.4 Function
			25.2.5 Mechanism of action
			25.2.6 Therapeutics
		25.3 Angiotensin II
			25.3.1 Background
			25.3.2 Genetics and translation
			25.3.3 Distribution
			25.3.4 Function
			25.3.5 Mechanism of action
			25.3.6 Therapeutics
		25.4 Endothelin
			25.4.1 Background
			25.4.2 Genetics and translation
			25.4.3 Distribution
			25.4.4 Function
			25.4.5 Mechanism of action
			25.4.6 Therapeutics
		25.5 Bradykinin
			25.5.1 Background
			25.5.2 Genetics and translation
			25.5.3 Distribution
			25.5.4 Function
			25.5.5 Mechanism of action
			25.5.6 Therapeutics
		25.6 Natriuretic peptides
			25.6.1 Background
			25.6.2 Atrial natriuretic peptide
			25.6.3 Carperitide
			25.6.4 B-type natriuretic peptide
			25.6.5 Nesiretide
			25.6.6 C-type natriuretic peptide
			25.6.7 Dendroaspis natriuretic peptide
			25.6.8 Ventricular natriuretic peptide
			25.6.9 Urodilatin
			25.6.10 Vasonatrin
			25.6.11 Cenderitide
			25.6.12 CU-NP
			25.6.13 M-ANP
			25.6.14 ANX042
			25.6.15 Lebetins
		25.7 Urotensin II
			25.7.1 Background
			25.7.2 Genetics and translation
			25.7.3 Mechanism of action
			25.7.4 Functions
			25.7.5 Therapeutics
		25.8 Conclusions
		Funding
		References
	26 Noncardiovascular-derived therapeutic peptidomimetics in cardiovascular disease
		26.1 Introduction
		26.2 Oxytocin and vasopressin
			26.2.1 Background
			26.2.2 Genetics and translation
			26.2.3 Distribution
			26.2.4 Function
			26.2.5 Mechanism of action
			26.2.6 Therapeutics
		26.3 Calcitonin gene-related protein
			26.3.1 Background
			26.3.2 Genetics and translation
			26.3.3 Distribution
			26.3.4 Function and pathological implications
			26.3.5 Mechanism of action
			26.3.6 Therapeutics
		26.4 Amylin
			26.4.1 Background
			26.4.2 Genetics and translation
			26.4.3 Distribution
			26.4.4 Function and pathological implications
			26.4.5 Mechanism of action
			26.4.6 Therapeutics
		26.5 Vasoactive intestinal peptide
			26.5.1 Background
			26.5.2 Genetics and translation
			26.5.3 Distribution
			26.5.4 Function
			26.5.5 Mechanism of action
			26.5.6 Therapeutics
		26.6 Glucagon-like peptide-1
			26.6.1 Background
			26.6.2 Genetics and translation
			26.6.3 Distribution
			26.6.4 Function
			26.6.5 Mechanism of action
			26.6.6 Therapeutics
		26.7 Ghrelin
			26.7.1 Background
			26.7.2 Genetics and translation
			26.7.3 Distribution
			26.7.4 Function
			26.7.5 Mechanism of action
			26.7.6 Therapeutics
		26.8 Salusins
			26.8.1 Background
			26.8.2 Genetics and translation
			26.8.3 Distribution
			26.8.4 Function and pathological implications
			26.8.5 Mechanism of action
			26.8.6 Therapeutics
		26.9 Apelin/APJ system
			26.9.1 Background
			26.9.2 Genetics and translation
			26.9.3 Distribution
			26.9.4 Mechanism of action
			26.9.5 Function
			26.9.6 Pathophysiology
			26.9.7 Therapeutics
		26.10 Urocortin
			26.10.1 Background
			26.10.2 Genetics and translation
			26.10.3 Distribution
			26.10.4 Mechanism of action
			26.10.5 Function
			26.10.6 Therapeutics
		26.11 Conclusion
		Funding
		References
5 Drug development
	27 Clinical and preclinical data on therapeutic peptides
		27.1 Introduction: the evolution of peptide therapeutics
		27.2 Classification of peptides
			27.2.1 Cell-penetrating peptides
			27.2.2 Cell-targeting peptides
			27.2.3 Therapeutic and diagnostic agents
			27.2.4 Direct cellular penetration
			27.2.5 Endocytosis
		27.3 Peptide drug market and preclinical data
			27.3.1 Systemically absorbed oral peptides
				27.3.1.1 Cyclosporin A
				27.3.1.2 Desmopressin acetate (DDVAP)
				27.3.1.3 Taltirelin
				27.3.1.4 Reduced l-glutathione
				27.3.1.5 Linaclotide
				27.3.1.6 Vancomycin
				27.3.1.7 Tyrothricin
		27.4 The future of peptide therapeutics
		27.5 Concluding remarks
		References
	28 Therapeutic peptides: market and manufacturing
		28.1 Historical perspectives on the therapeutic peptide market
		28.2 Current perspectives on the therapeutic peptide market
		28.3 Assessing the market value of therapeutic peptides
		28.4 Approaches to manufacturing therapeutic peptides
		28.5 Innovations in therapeutic peptide discovery and manufacturing
		28.6 Conclusions
		References
		Further reading
	29 Future perspectives on peptide therapeutics
		29.1 Introduction
		29.2 Proteolytic stability
			29.2.1 Rational design
			29.2.2 Identification of cleavage site(s)
				29.2.2.1 Modification of amino and carboxy termini
				29.2.2.2 D-amino acid incorporation
				29.2.2.3 Amino acid modification
			29.2.3 Peptidomimetics
				29.2.3.1 N-methylation
				29.2.3.2 α-Methylation (Aib)
				29.2.3.3 Aza modifications
				29.2.3.4 Cyclization
		29.3 Renal clearance
			29.3.1 PEGylation
			29.3.2 Lipidation
			29.3.3 Plasma protein fusion to extend circulation times
				29.3.3.1 Albumin conjugation
				29.3.3.2 Conjugation to immunoglobulin G
		29.4 Oral bioavailability
			29.4.1 Technologies for oral delivery of peptides
				29.4.1.1 Permeation enhancers
				29.4.1.2 Microneedle approaches
		29.5 Peptide therapeutics targeting the central nervous system
		29.6 Future perspectives
		References
Index
Back Cover