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
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