Peptide-Based Drug Design

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The Spot Technique 65 following rule must be kept in mind: the longer the peptide, the more difficulties arise during coupling—the number of possible side reactions increases and peptide purity decreases dramatically! 11. Since it is unlikely for one to be able to synthesize all possible sequences on a single spot, do not start synthesis of a combinatorial library with more than 6 mixture positions. If necessary, start to screen 8mer peptides (6 mixture + 2 deconvoluted positions) and extend the peptide length with each synthesis round by extending the deconvoluted positions and maintaining the number of mixed positions (e.g., 6 mixture + 4 deconvoluted positions). 12. Because of possible strong side reactions during the probing, avoid the use of cysteines in the first synthesis and screening rounds at defined amino acid positions. 13. After incubation, if a spot signal also shows a corresponding spot signal by reflection on a virtual diagonal (Pos.1,1 to pos. x,x), it is possible that these two signals are caused by unspecific binding. 14. Avoid exposure to daylight at all steps using the chemiluminescence mixture. In particular, when using X-ray film for detection a red light room should be used. 15. Use of towels made of nonrecycled paper is recommended. Using recycled towels could lead to disturbances in detection by reactions with trace materials in the paper. 16. After probing, the membrane must remain wet for regeneration. A previously dried membrane is more difficult to regenerate than a wet one. 17. From time to time incomplete regeneration could occur. Therefore, it is recommended to always use new membranes; if not, then the membrane should be probed first with the control and then with the protein sample. For further probing with the same membrane, completeness of the regeneration should be checked by repeating the detection without the protein sample. All detectable signals should be found in the previous control. Additional signals seen with the sample probe should have disappeared. Stained spots are generally very hard to regenerate. 18. Commonly used biotinylating reagents are usually amine reactive. For biotinylation of your protein, do not dissolve your protein sample in amine-containing buffers, such as TBS, TBS-T, or PBS-T. References 1. Frank, R. (1992) Spot-synthesis: An easy technique for the positionally addressable, parallel chemical synthesis on a membrane support. Tetrahedron 48, 9217–9232. 2. Kramer, A. and Schneider-Mergener, J. (1998) Synthesis and application of peptide libraries bound to continuous cellulose membranes. Methods Mol. Biol. 87, 25–39. 3. Gausepohl, H. and Behn, C. (2002) Automated synthesis of solid-phase bound peptides. In: Peptide Arrays on Membrane Support, eds. J. Koch and M. Mahler, pp. 55–68. Berlin: Springer-Verlag. 4. Molina, F., Laune, D., Gougat, C., Pau, B., and Granier, C. (1996) Improved performances of spot multiple peptide synthesis. Peptide Res. 9, 151–155.
66 Winkler and Campbell 5. Kramer, A., Reineke, U., Dong, L., et al. (1999) Spot-synthesis: observations and optimizations. J. Peptide Res. 54, 319–327. 6. Frank, R. (2002) The SPOT-synthesis technique. Synthetic peptide arrays on membrane supports-principles and applications. J. Immunol. Methods 267, 13–26. 7. Blackwell, H.E. (2006) Hitting the SPOT: small-molecule macroarrays advance combinatorial synthesis. Curr. Opin. Chem. Biol. 10, 203–212. 8. Frank, R., Hoffmann, S., Overwin, H., Behn, C., and Gausepohl, H. (1996) Easy preparation of synthetic peptide repertoires for immunological studies utilizing SPOT synthesis. In: Peptides in Immunology, ed. C.H. Schneider, pp. 197–204. New York: John Wiley & Sons, Ltd. 9. Wenschuh, H., Volkmer-Engert, R., Schmidt, M., Schulz, M., Schneider- Mergener, J., and Reineke, U. (2000) Coherent membrane supports for parallel microsynthesis and screening of bioactive peptides. Biopolymers (Peptide Science) 55, 188–206. 10. Reineke, U., Volkmer-Engert, R., and Schneider-Mergener, J. (2001) Applications of peptide arrays prepared by the SPOT-technology. Curr. Opin. Biotechnol. 12, 59–64. 11. Frank, R. and Schneider-Mergener, J. (2002) SPOT synthesis—scope of applications. In: Peptide Arrays on Membrane Support, eds. J. Koch and M. Mahler, pp 1–22. Berlin Heidelberg: Springer-Verlag. 12. Hilpert, K., Winkler, D.F.H., and Hancock, R.E.W. (2007) Cellulose-bound peptide arrays: Preparation and applications. Biotechnol. Genetic Eng. Rev. 24, 31–106. 13. Reineke, U., Sabat, R., Volk, H.-D., and Schneider-Mergener, J. (1998) Mapping of the interleukin-10/interleukin-10 receptor combining site. Protein Sci. 7, 951–960. 14. Otvos Jr., L., Pease, A.M., Bokonyi, K., et al. (2000) In situ stimulation of a T helper cell hybrodoma with a cellulose-bound peptide antigen. J. Immunol. Methods 233, 95–1051. 15. Bräuning, R., Mahler, M., Hügle-Dörr, B., Blüthner, M., Koch, J., and Petersen, G. (2002) Immobilized peptides to study protein-protein interactions—potential and pitfalls. In: Peptide Arrays on Membrane Support, eds. J. Koch and M. Mahler, pp.153–163. Berlin: Springer-Verlag. 16. Martens, W., Greiser-Wilke, I., Harder, T.C., et al. (1995) Spot synthesis of overlapping peptides on paper membrane supports enables the identification of linear monoclonal antibody binding determinants on morbillivirus phosphoproteins. Vet. Microbiol. 44, 289–298. 17. Santona, A., Carta, F., Fraghi, P., and Turrini, F. (2002) Mapping antigenic sites of an immunodominant surface lipoprotein of Mycoplasma agalactiae, AvgC, with the use of synthetic peptides. Infect. Immun. 70, 171–176. 18. Fields, G.B. and Noble, R.L. (1990) Solid phase synthesis utilizing 9-fluorenylmethoxycarbonyl amino acids. Int. J. Peptide Protein Res. 35, 161–214. 19. Zander, N. and Gausepohl, H. (2002) Chemistry of Fmoc peptide synthesis on membranes. In: Peptide Arrays on Membrane Support, eds. J. Koch and M. Mahler, pp. 23–39.Berlin: Springer-Verlag.
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Peptide-Based Drug Design
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METHODS IN MOLECULAR BIOLOGY TM Pep
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Preface Natural products chemistry
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Contents Preface...................
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Contributors Nikolinka Antcheva •
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Contributors xi Alessandro Tossi
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2 Otvos advance of computer power a
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4 Otvos see derivatives active in b
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6 Otvos was designed based on ligan
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8 Otvos 27. Borghouts, C., Kunz, C.
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10 Bulet Key Words: Invertebrate im
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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
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 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 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,
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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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