Peptide-Based Drug Design

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Glycosylated Amino Acid Synthesis 199 BzO BzO O BzO SEt + CH 2 -OH Cbz-NH-CH-COOBn DMTST TMSOTf (80%) BzO BzO O BzO O CH2 -CH COOBn NH-Cbz Fig. 10. Synthesis of �-D-Xyl-(1→O)-Ser derivative using thioglycoside derived from xylose (85). 2. Add thiophenol (1.5 eq), followed by Lewis acid, BF3·Et2O (3 eq), and stir overnight at room temperature. 3. Wash reaction mixture two times with saturated aqueous sodium bicarbonate (NaHCO3) and then with water. 4. Combine filtrates, evaporate and purify by flash chromatography. 3.2.4.2. THIOGLYCOSIDE METHOD 1. Dissolve the glycosyl donor (1 eq) and acceptor (1 eq) in dichloromethane and stir with activated molecular sieves (4 ˚A) under an inert atmosphere at room temperature (see Note 2). 2. Add DMTST (1.5 eq) and stir overnight at room temperature (see Note 12). 3. At the same temperature add N,N-diisopropylethylamine (1.5 eq) to neutralize the acid. 4. Filter reaction mixture over Celite and wash the Celite well with CH2Cl2. 5. Wash the organic filtrate with saturated aqueous NaHCO3. 6. Combine filtrates, evaporate and purify by flash chromatography. 3.3. N-Glycosylated Amino Acids N-Glycosidic linkage is commonly formed between a glycosyl amine and an activated aspartic acid derivative instead of glycosylation of asparagine (Scheme 3). Therefore, the first step toward the synthesis of N-glycosylated amino acids is the preparation of glycosyl amines. Two of the most commonly used procedures for the synthesis of glycosyl amines include the reduction of glycosyl azides and the treatment of reducing sugars with saturated ammonium OR1 R O 1O NH R1O 2 AcNH R 1 = H or protecting group + R 2 HN COOR 3 COOX X = Activating group R 2 ,R 3 = Protecting group R1O R1O OR1 O H N AcNH Scheme. 3. Formation of N-glycosidic linkage. O NH-R 2 N-glycosidic linkage COOR 3
200 Cudic and Burstein AcO AcO O AcNH X X = Cl, Br OAc NaN 3 ,Bu 4 N + HSO 4 – AcO AcO OAc O AcNH N 3 OAc H2 , Raney-Ni AcO AcO O AcNH Fig. 11. Synthesis of glycosyl amine by reduction of glycosyl azide (88,95). OH HO HO O O AcNH HO OH O AcNH OH NH 4 + HCO3 – , aq.NH3 NH 2 OH OH HO O HO O O AcNH HO NH2 AcNH Fig. 12. Synthesis of glycosyl amine by amination of reducing sugar (chitobiose) (97). a) b) AcO AcO OAc O AcNH NH 2 Fmoc-Asp-OtBu DCC, HOBt OH OH HO O HO O O AcNH HO NH2 AcNH AcO AcO OAc O AcNH NH Fmoc-Asp(OtBu)-COOPfp TFA O COOtBu NHFmoc OH OH HO O HO O O AcNH HO NH AcNH O COOH NHFmoc Fig. 13. Synthesis of �-linked asparagines glycosides: (a) dicyclohexylcarbodiimide (DCC) and 1-hydroxybenzotriazole (HOBt) coupling (98), (b) pentafluorophenyl (OPfp) ester of aspartic acid derivative coupling (97). hydrogen carbonate. Glycosyl azides are most often obtained from the corresponding glycosyl halides (86–88) and then reduced to glycosyl amines by several available approaches (87,89–95) (Fig. 11). The second route to glycosyl amine involves the introduction of the amino group at the reducing end of an unprotected carbohydrate in the presence of saturated ammonium bicarbonate (96) (Fig. 12). Formation of an amide bond between a glycosyl amine and aspartic acid derivative or an aspartic acid–containing peptide can be than achieved by methods used for the formation of a peptide bond (Fig. 13) (40,97–99). 3.3.1. Synthesis of Glycosylamine from Glycosyl Azides 1. Prepare glycosyl halide according to steps 1–5 from Subheading 3.2.1.1. 2. Dissolve glycosyl halide (1 eq) in DMF and add NaN3 (1.5 eq) and stir overnight at 80◦C.
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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
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14 Bulet 2.5.2.1. MALDI-TOF-MS 1. M
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16 Bulet 7. Small-volume low-protei
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18 Bulet 3. Centrifuge between 8000
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20 Bulet internal diameter). Increa
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22 Bulet interest. As no instrument
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24 Bulet 3. Incubate the plates in
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26 Bulet bioactive peptides from th
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28 Bulet 21. Chernysh, S., Kim, S.I
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3 Sequence Analysis of Antimicrobia
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Sequence Analysis of Antimicrobial
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4 The Spot Technique: Synthesis and
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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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Page 158 and 159: 148 Hilpert et al. of substituting
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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 186 and 187: 10 Serum Stability of Peptides Håv
Page 188 and 189: Serum Stability of Peptides 179 2.
Page 192 and 193: Serum Stability of Peptides 183 �
Page 196 and 197: 11 Preparation of Glycosylated Amin
Page 198 and 199: Glycosylated Amino Acid Synthesis 1
Page 218 and 219: 12 Synthesis of O-Phosphopeptides o
Page 220 and 221: Solid-Phase Synthesis of O-Phosphop
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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
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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
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Page 256 and 257: 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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