Peptide-Based Drug Design

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Contributors xi Alessandro Tossi • Department of Life Sciences, University of Trieste, Trieste, Italy John D. Wade • Howard Florey Institute and School of Chemistry, University of Melbourne, Parkville, Victoria, Australia Jan-Christoph Westermann • Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia Dirk F.H.Winkler • Peptide Array Facility of the Brain Research Centre, University of British Columbia, Vancouver, British Columbia, Canada Weiguang Zeng • Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria, Australia
1 Peptide-Based Drug Design: Here and Now Laszlo Otvos, Jr. Summary After many years of stagnation, peptide therapeutics once again became the focus of innovative drug development efforts backed up by venture funds and biotechnology companies. Designer peptide drugs overcome the unattractive pharmacological properties of native peptides and protein fragments and frequently feature nonnatural amino acid or backbone replacements, cyclic or multimeric structures, or peptidic or nonpeptidic delivery modules. With their high specificity and low toxicity profile, biologicals offer viable alternatives to small molecule therapeutics. The development of peptide drugs requires specific considerations of this family of biopolymers. Historically, peptide vaccines to viral infections and antibacterial peptides led the way in clinical development, but recently many other diseases have been targeted, including the big sellers AIDS, cancer, and Alzheimer’s disease. This book gives practical advice to the most important steps in peptide-based drug development such as isolation, purification, characterization, interaction with targets, structural analysis, stability studies, assessment of biodistribution and pharmacological parameters, sequence modifications, and high throughput screening. This brief overview provides historical background for each of the listed techniques and diseases. Key Words: Backbone; design; nonnatural amino acids; pharmacology; recognition; stability; toxicity. The vast majority of current designer drugs target biopolymers or biopolymer interactions. There is no surprise here: the more we know about complex biochemical pathways, the larger the number of potential target proteins, nucleic acids, or lipidic structures that surface and offer themselves for agonist or antagonist development. In many cases a protein fragment, either part of the unprocessed protein or a cleaved piece, can be identified that serves as a ligand or the target itself. Naturally occurring peptide drugs are just the beginning. With the From: Methods in Molecular Biology, vol. 494: Peptide-Based Drug Design Edited by: L. Otvos, DOI: 10.1007/978-1-59745-419-3 1, © Humana Press, New York, NY 1
Page 2 and 3: Peptide-Based Drug Design
Page 4 and 5: METHODS IN MOLECULAR BIOLOGY TM Pep
Page 6 and 7: Preface Natural products chemistry
Page 8 and 9: Contents Preface...................
Page 10 and 11: Contributors Nikolinka Antcheva •
Page 14 and 15: 2 Otvos advance of computer power a
Page 16 and 17: 4 Otvos see derivatives active in b
Page 18 and 19: 6 Otvos was designed based on ligan
Page 20 and 21: 8 Otvos 27. Borghouts, C., Kunz, C.
Page 22 and 23: 10 Bulet Key Words: Invertebrate im
Page 24 and 25: 12 Bulet 6. 5 �L or higher volume
Page 26 and 27: 14 Bulet 2.5.2.1. MALDI-TOF-MS 1. M
Page 28 and 29: 16 Bulet 7. Small-volume low-protei
Page 30 and 31: 18 Bulet 3. Centrifuge between 8000
Page 32 and 33: 20 Bulet internal diameter). Increa
Page 34 and 35: 22 Bulet interest. As no instrument
Page 36 and 37: 24 Bulet 3. Incubate the plates in
Page 38 and 39: 26 Bulet bioactive peptides from th
Page 40 and 41: 28 Bulet 21. Chernysh, S., Kim, S.I
Page 42 and 43: 3 Sequence Analysis of Antimicrobia
Page 44 and 45: Sequence Analysis of Antimicrobial
Page 58 and 59: 4 The Spot Technique: Synthesis and
Page 60 and 61: The Spot Technique 49 3. For amine
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The Spot Technique 51 2. Biotinylat
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The Spot Technique 53 the solutions
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The Spot Technique 55 solution. Ens
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The Spot Technique 57 (see Fig. 3)
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The Spot Technique 59 Fig. 5. Princ
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The Spot Technique 61 library, the
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The Spot Technique 63 7. Regenerati
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The Spot Technique 65 following rul
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The Spot Technique 67 20. Atherton,
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The Spot Technique 69 50. Bolger, G
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5 Analysis of A� Interactions Usi
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Analysis of Aβ Interactions 73 are
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Analysis of Aβ Interactions 75 Ana
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Analysis of Aβ Interactions 77 3.
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6 NMR in Peptide Drug Development J
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NMR of Peptides 89 usually require
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NMR of Peptides 91 limiting the siz
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NMR of Peptides 93 and STD NMR expe
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NMR of Peptides 95 The basis of the
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NMR of Peptides 97 Fig. 5. Overlay
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NMR of Peptides 99 Fig. 7. Schemati
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NMR of Peptides 101 4.4.2. Saturati
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NMR of Peptides 103 4.6. Diffusion
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NMR of Peptides 105 Fig. 13. Propos
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NMR of Peptides 107 protein prevent
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NMR of Peptides 109 6. Wuthrich, K.
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NMR of Peptides 111 45. Morris, K.
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NMR of Peptides 113 78. Aumailley,
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116 Copps et al. Fig. 1. Potential
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118 Copps et al. Fig. 2. Flowchart
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120 Copps et al. 10. In accordance
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122 Copps et al. Fig. 3. DSSP for g
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124 Copps et al. ingly with the sam
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126 Copps et al. 19. Essman, U., Pe
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128 Hilpert et al. Key Words: Scree
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130 Hilpert et al. Table 1 (Continu
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132 Hilpert et al. different natura
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134 Hilpert et al. wt A C D E F …
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136 Hilpert et al. methods primaril
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144 Hilpert et al. Table 3 Summary
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148 Hilpert et al. of substituting
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150 Hilpert et al. in models that c
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152 Hilpert et al. than control. Gi
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154 Hilpert et al. Table 4 Accuracy
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156 Hilpert et al. 25. Pini, A., Gi
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158 Hilpert et al. 55. Giacometti,
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9 Investigating the Mode of Action
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Proline-Rich Antimicrobial Peptides
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10 Serum Stability of Peptides Håv
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Serum Stability of Peptides 179 2.
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Serum Stability of Peptides 183 �
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11 Preparation of Glycosylated Amin
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Glycosylated Amino Acid Synthesis 1
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12 Synthesis of O-Phosphopeptides o
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Solid-Phase Synthesis of O-Phosphop
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13 Peptidomimetics: Fmoc Solid-Phas
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Peptidomimetics 225 O O R S N H Pep
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Peptidomimetics 227 not without its
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Peptidomimetics 229 Oxidation step:
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Peptidomimetics 231 of peptidosulfo
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Peptidomimetics 233 8. Allow the re
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Peptidomimetics 235 3.3.2. Solid-Ph
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Peptidomimetics 237 On the other ha
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Peptidomimetics 239 nitrogen (73).
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Peptidomimetics 241 3. Cover the re
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Peptidomimetics 243 efficient synth
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Peptidomimetics 245 55. Alsina, J.,
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14 Synthesis of Toll-Like Receptor-
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Lipopeptides 249 2. Materials 2.1.
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Lipopeptides 251 Fig. 1. Structural
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Lipopeptides 253 8. To enable lipid
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Lipopeptides 255 Representative res
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Lipopeptides 257 Fig. 2. Immunogeni
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Lipopeptides 259 8. A large plastic
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Lipopeptides 261 26. Nardin, E.H.,
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264 Otvos response, synthetic pepti
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266 Otvos Fig. 3. Schematic present
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268 Otvos 3. Methods The main goal
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270 Otvos 3.2.3. Purification and Q
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272 Otvos 6. Meyer, D., and Torres,
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16 Cysteine-Containing Fusion Tag f
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Targeted Therapeutic and Imaging Ag
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Index A A� peptides aggregation a
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Index 297 phosphopeptides influenci
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Index 299 for genetically synthetic
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Index 301 peptidosulfonamide, disad
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Index 303 solid phase, 180, 214 sul
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Peptide-Based Drug Design

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