Peptide-Based Drug Design

More documents

Recommendations

Info

Lipopeptides 261 26. Nardin, E.H., Calvo-Calle, J.M., Oliveira, G.A., et al. (1998) Plasmodium falciparum polyoximes: highly immunogenic synthetic vaccines constructed by chemoselective ligation of repeat B-cell epitopes and a universal T-cell epitope of CS protein. Vaccine 16(6), 590–600. 27. Obert, M., Pleuger, H., Hanagarth, H.G., et al. (1998) Protection of mice against SV40 tumours by Pam3Cys, MTP-PE and Pam3Cys conjugated with the SV40 T antigen-derived peptide, K(698)-T(708). Vaccine 16(2–3), 161–169. 28. Mora, A.L. and Tam, J.P. (1998) Controlled lipidation and encapsulation of peptides as a useful approach to mucosal immunizations. J. Immunol. 161(7), 3616–3623. 29. Shimizu, T., Ohtsuka, Y., Yanagihara, Y., Kurimura, M., Takemoto, M., and Achiwa, K. (1991) Comparison of biologic activities of synthetic lipopentapeptide analogs of bacterial lipoprotein in mice. Mol. Biother. 3(1), 46–50. 30. Delves, P.J., Lund, T., and Roitt, I.M. (2002) Antifertility vaccines. Trends Immunol. 23(4), 213–219. 31. Oonk, H.B., Turkstra, J.A., Schaaper, W.M., et al. (1998) New GnRH-like peptide construct to optimize efficient immunocastration of male pigs by immunoneutralization of GnRH. Vaccine 16(11–12), 1074–1082. 32. Ferro, V.A. and Stimson, W.H. (1997) Immunoneutralisation of gonadotrophin releasing hormone: a potential treatment for oestrogen-dependent breast cancer. Eur. J. Cancer 33(9), 1468–1478. 33. Talwar, G.P. (1999) Vaccines and passive immunological approaches for the control of fertility and hormone-dependent cancers. Immunol. Rev. 171, 173–192. 34. Ghosh, S., Walker, J., and Jackson, D.C. (2001) Identification of canine helper T-cell epitopes from the fusion protein of canine distemper virus. Immunology 104(1), 58–66. 35. Wade, J.D., Bedford, J., Sheppard, R.C., and Tregear, G.W. (1991) DBU as an N alpha-deprotecting reagent for the fluorenylmethoxycarbonyl group in continuous flow solid-phase peptide synthesis. Pept. Res. 4(3), 194–199.
15 Synthesis of a Multivalent, Multiepitope Vaccine Construct Laszlo Otvos, Jr. Summary A major challenge to contemporary peptide chemistry is to reproduce highly complex active sites or complexes of native proteins. In addition to the need for the combination of different peptide fragments, true protein mimics designed for therapeutic use frequently require the incorporation of multiple copies of given active domains in a biologically relevant spatial arrangement. Perhaps the best examples for this line of drug design are subunit vaccine candidates against extracellular domains of ion-channel proteins. One of our earlier constructs containing four copies of the ectodomain of the M2 protein of influenza virus together with two independent T-helper cell epitopes induced protective antibody production in mice. Here I describe an improved synthesis of the M2-based multiepitope and multivalent peptide construct. In general, the synthetic strategy outlined here can serve as a model for the orthogonal N-terminal and side-chain– protecting scheme during the preparation of large, complex peptides or small, engineered proteins. Key Words: Automated peptide synthesis; influenza virus; oligolysine scaffold; orthogonal side-chain protection; protective antibody; T-helper cell determinant. 1. Introduction Peptide fragments represent the biologically active domains of native proteins. However, many recognition processes require the presence of multiple independent protein fragments, co-activators, or chaperones (1). In addition, it was long considered that peptides without carrier modules are unable to enter cells (2), although since the turn of the millennium this assumption has been increasingly challenged (3). Thus, to elicit the desired and full biological From: Methods in Molecular Biology, vol. 494: Peptide-Based Drug Design Edited by: L. Otvos, DOI: 10.1007/978-1-59745-419-3 15, © Humana Press, New York, NY 263
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 12 and 13:
Contributors xi Alessandro Tossi
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 46 and 47:
Page 48 and 49:
Page 50 and 51:
Page 52 and 53:
Page 54 and 55:
Page 56 and 57:
Page 58 and 59:
4 The Spot Technique: Synthesis and
Page 60 and 61:
The Spot Technique 49 3. For amine
Page 62 and 63:
The Spot Technique 51 2. Biotinylat
Page 64 and 65:
The Spot Technique 53 the solutions
Page 66 and 67:
The Spot Technique 55 solution. Ens
Page 68 and 69:
The Spot Technique 57 (see Fig. 3)
Page 70 and 71:
The Spot Technique 59 Fig. 5. Princ
Page 72 and 73:
The Spot Technique 61 library, the
Page 74 and 75:
The Spot Technique 63 7. Regenerati
Page 76 and 77:
The Spot Technique 65 following rul
Page 78 and 79:
The Spot Technique 67 20. Atherton,
Page 80 and 81:
The Spot Technique 69 50. Bolger, G
Page 82 and 83:
5 Analysis of A� Interactions Usi
Page 84 and 85:
Analysis of Aβ Interactions 73 are
Page 86 and 87:
Analysis of Aβ Interactions 75 Ana
Page 88 and 89:
Analysis of Aβ Interactions 77 3.
Page 90 and 91:
Page 92 and 93:
Page 94 and 95:
Page 96 and 97:
Page 98 and 99:
6 NMR in Peptide Drug Development J
Page 100 and 101:
NMR of Peptides 89 usually require
Page 102 and 103:
NMR of Peptides 91 limiting the siz
Page 104 and 105:
NMR of Peptides 93 and STD NMR expe
Page 106 and 107:
NMR of Peptides 95 The basis of the
Page 108 and 109:
NMR of Peptides 97 Fig. 5. Overlay
Page 110 and 111:
NMR of Peptides 99 Fig. 7. Schemati
Page 112 and 113:
NMR of Peptides 101 4.4.2. Saturati
Page 114 and 115:
NMR of Peptides 103 4.6. Diffusion
Page 116 and 117:
NMR of Peptides 105 Fig. 13. Propos
Page 118 and 119:
NMR of Peptides 107 protein prevent
Page 120 and 121:
NMR of Peptides 109 6. Wuthrich, K.
Page 122 and 123:
NMR of Peptides 111 45. Morris, K.
Page 124 and 125:
NMR of Peptides 113 78. Aumailley,
Page 126 and 127:
116 Copps et al. Fig. 1. Potential
Page 128 and 129:
118 Copps et al. Fig. 2. Flowchart
Page 130 and 131:
120 Copps et al. 10. In accordance
Page 132 and 133:
122 Copps et al. Fig. 3. DSSP for g
Page 134 and 135:
124 Copps et al. ingly with the sam
Page 136 and 137:
126 Copps et al. 19. Essman, U., Pe
Page 138 and 139:
128 Hilpert et al. Key Words: Scree
Page 140 and 141:
130 Hilpert et al. Table 1 (Continu
Page 142 and 143:
132 Hilpert et al. different natura
Page 144 and 145:
134 Hilpert et al. wt A C D E F …
Page 146 and 147:
136 Hilpert et al. methods primaril
Page 148 and 149:
Page 150 and 151:
Page 152 and 153:
Page 154 and 155:
144 Hilpert et al. Table 3 Summary
Page 156 and 157:
Page 158 and 159:
148 Hilpert et al. of substituting
Page 160 and 161:
150 Hilpert et al. in models that c
Page 162 and 163:
152 Hilpert et al. than control. Gi
Page 164 and 165:
154 Hilpert et al. Table 4 Accuracy
Page 166 and 167:
156 Hilpert et al. 25. Pini, A., Gi
Page 168 and 169:
158 Hilpert et al. 55. Giacometti,
Page 170 and 171:
9 Investigating the Mode of Action
Page 172 and 173:
Proline-Rich Antimicrobial Peptides
Page 174 and 175:
Page 176 and 177:
Page 178 and 179:
Page 180 and 181:
Page 182 and 183:
Page 184 and 185:
Page 186 and 187:
10 Serum Stability of Peptides Håv
Page 188 and 189:
Serum Stability of Peptides 179 2.
Page 190 and 191:
Page 192 and 193:
Serum Stability of Peptides 183 �
Page 194 and 195:
Page 196 and 197:
11 Preparation of Glycosylated Amin
Page 198 and 199:
Glycosylated Amino Acid Synthesis 1
Page 200 and 201:
Page 202 and 203:
Page 204 and 205:
Page 206 and 207:
Page 208 and 209:
Page 210 and 211:
Page 212 and 213:
Page 214 and 215:
Page 216 and 217:
Page 218 and 219:
12 Synthesis of O-Phosphopeptides o
Page 220 and 221: Solid-Phase Synthesis of O-Phosphop
Page 232 and 233: 13 Peptidomimetics: Fmoc Solid-Phas
Page 234 and 235: Peptidomimetics 225 O O R S N H Pep
Page 236 and 237: Peptidomimetics 227 not without its
Page 238 and 239: Peptidomimetics 229 Oxidation step:
Page 240 and 241: Peptidomimetics 231 of peptidosulfo
Page 242 and 243: Peptidomimetics 233 8. Allow the re
Page 244 and 245: Peptidomimetics 235 3.3.2. Solid-Ph
Page 246 and 247: Peptidomimetics 237 On the other ha
Page 248 and 249: Peptidomimetics 239 nitrogen (73).
Page 250 and 251: Peptidomimetics 241 3. Cover the re
Page 252 and 253: Peptidomimetics 243 efficient synth
Page 254 and 255: Peptidomimetics 245 55. Alsina, J.,
Page 256 and 257: 14 Synthesis of Toll-Like Receptor-
Page 258 and 259: Lipopeptides 249 2. Materials 2.1.
Page 260 and 261: Lipopeptides 251 Fig. 1. Structural
Page 262 and 263: Lipopeptides 253 8. To enable lipid
Page 264 and 265: Lipopeptides 255 Representative res
Page 266 and 267: Lipopeptides 257 Fig. 2. Immunogeni
Page 268 and 269: Lipopeptides 259 8. A large plastic
Page 272 and 273: 264 Otvos response, synthetic pepti
Page 274 and 275: 266 Otvos Fig. 3. Schematic present
Page 276 and 277: 268 Otvos 3. Methods The main goal
Page 278 and 279: 270 Otvos 3.2.3. Purification and Q
Page 280 and 281: 272 Otvos 6. Meyer, D., and Torres,
Page 282 and 283: 16 Cysteine-Containing Fusion Tag f
Page 284 and 285: Targeted Therapeutic and Imaging Ag
Page 302 and 303: Index A A� peptides aggregation a
Page 304 and 305: Index 297 phosphopeptides influenci
Page 306 and 307: Index 299 for genetically synthetic
Page 308 and 309: Index 301 peptidosulfonamide, disad
Page 310: Index 303 solid phase, 180, 214 sul
show all

Peptide-Based Drug Design

Create successful ePaper yourself

Delete template?

Save as template?