Peptide and Protein Design for Biopharmaceutical Applications

✍ Scribed by Knud Jensen

• Publisher: Wiley
• Year: 2009
• Tongue: English
• Leaves: 309
• Edition: 1
• Category: Library

✦ Synopsis

Peptides serve as effective drugs in the clinic today. However the inherent drawbacks of peptide structures can limit their efficacy as drugs. To overcome this researchers are developing new methods to create ‘tailor-made’ peptides and proteins with improved pharmacological properties.Design of Peptides and Proteins provides an overview of the experimental and computational methods for peptide and protein design, with an emphasis on specific applications for therapeutics and biomedical research. Topics covered include:Computer modeling of peptides and proteinsPeptidomimeticsDesign and synthesis of cyclic peptidesCarbohydrates in peptide and protein designDe novo design of peptides and proteinsMedical development applicationsAn extended case study – the design of insulin variantsDesign of Peptides and Proteins presents the state-of-the-art of this exciting approach for therapeutics, with contributions from international experts. It is an essential resource for academic and industrial scientists in the fields of peptide and protein drug design, biomedicine, biochemistry, biophysics, molecular modelling, synthetic organic chemistry and medicinal/pharmaceutical chemistry.

✦ Table of Contents

fmatter......Page 1
fpref.pdf......Page 0
Preface......Page 8
ins......Page 12
Introduction......Page 18
Acknowledgements......Page 21
The Importance of Computational Approaches......Page 22
Tools and Procedures: Force Fields and Sampling......Page 25
Force fields......Page 26
Scoring functions......Page 34
Sampling......Page 37
The 3D Pharmacophore Model for FC131......Page 48
Caveats and comments......Page 51
A 3D Model of the TM Region of CXCR4......Page 52
Caveats and comments......Page 54
Docking of FC131 to CXCR4......Page 55
Caveats and comments......Page 57
Conclusion......Page 65
beta-strand Mimetics......Page 91
beta-sheet nucleating templates......Page 92
Macrocyclic beta-strand mimics......Page 98
Backbone-modified strand mimetics......Page 100
Topomimetics......Page 102
Helix Mimetics......Page 103
Helix nucleators......Page 104
Helix surface mimetics......Page 105
Conclusion......Page 148
General Advantages of Cyclic Peptide Structures......Page 149
Cyclosporin A as a prominent drug compound......Page 150
Further medium-sized and larger natural products......Page 151
General Considerations......Page 152
Possibilities of Peptide Cyclization......Page 153
Synthesis of Cyclic Peptides......Page 154
Peptide strand arrangements......Page 156
Peptide bond modifications......Page 157
Amino acid side-chain alterations......Page 159
Modifications in natural peptides......Page 160
Reductions in Conformational Space......Page 161
Peptide bonds in cis and trans orientation......Page 163
Turn structures and their relevance for biological activity......Page 164
Hydrogen-bond networks......Page 165
Backbone dynamics......Page 166
Methods for studying conformational features......Page 167
Reliability of structural models......Page 168
The influence of changes in amino acid chiralities......Page 169
The Dunitz-Waser Concept......Page 170
The Spatial Screening Technique......Page 171
General Strategy for Finding Active Hits......Page 172
Cilengitide as Integrin Inhibitor......Page 174
CXCR4 Antagonists......Page 178
Sandostatin and the Veber-Hirschmann Peptide as Examples of Rational Design......Page 179
Conclusion......Page 192
Biopharmaceutical Applications Of De Novo Design......Page 222
The alpha-helix......Page 223
Loops, Turns and Templates......Page 229
Computational Methods......Page 230
Coiled Coils......Page 231
3-helix bundles......Page 235
4-helix bundles......Page 238
alpha-helical metalloproteins......Page 239
Fluorous Interactions......Page 240
Additional Topics......Page 243
alpha-helical Structures in Biopharmaceutical Applications......Page 251
Foldamers in Biopharmaceutical Applications......Page 253
Conclusion......Page 264
Index......Page 302