TY - BOOK
T1 - Combinatorally Evolved Peptides: Targeting the Molecular Basis for Alzheimer's Disease
AU - Hansen, Jonas
PY - 2017
Y1 - 2017
N2 - In this thesis the potential for peptide-peptide interaction with the amyloid beta peptide Aβ42 associated with Alzheimer’s disease has been investigate. Accumulation of amyloid peptides has strong links to the debilitating condition. Modulation of their expression, aggregation and clearance remain subject to concentrated research, despite disappointing clinical trials. The interest in amyloid peptides extends beyond Alzheimer’s disease, following discoveries that the amyloid state is a more general behavior of oligopeptides and even entire proteins. Detailed structural information about interaction with this type of structures will therefore have application in designing new compounds to influences amyloid targets in a wide range of biological systems. In order to develop peptides for amyloid interaction, Fmoc-based solid phase peptide synthesis (SPPS) and combinatorial screening techniques have been utilized. The ability to harness the unpredictable molecular interaction of randomized peptides, to produce sequence specific binding partner is the promise of this methodology. The identified peptide hits were discovered to have a diverse composition. Detailed analysis by comprehensive on-beads binding studies revealed the strongest hits to be rather non-polar in nature, with binding constants in the nanomolar range. New reactions have also been developed for peptide chemistry on the HMBA linker. These include convenient methods for cleavage and simultaneous C-terminal functionalization of peptides, to form acids amides and esters. All reactions utilize the strong leaving group potential of the HMBA linker to facilitate nucleophilic attack. Generally esters were formed fast and efficiently using strong base and neat alcohol, with high purity of the target peptide esters. The tested amines were sufficiently nucleophilic to form the corresponding amides without activation. MIDA protected boryl aldehyde has been successfully used to synthesize linear and cyclic peptides containing a boronic acid peptoid functionality. The reductive amination of the boryl aldehyde with the N-terminus of peptides was effective on solid support and the MIDA group was determined to be stable towards peptide coupling conditions.
AB - In this thesis the potential for peptide-peptide interaction with the amyloid beta peptide Aβ42 associated with Alzheimer’s disease has been investigate. Accumulation of amyloid peptides has strong links to the debilitating condition. Modulation of their expression, aggregation and clearance remain subject to concentrated research, despite disappointing clinical trials. The interest in amyloid peptides extends beyond Alzheimer’s disease, following discoveries that the amyloid state is a more general behavior of oligopeptides and even entire proteins. Detailed structural information about interaction with this type of structures will therefore have application in designing new compounds to influences amyloid targets in a wide range of biological systems. In order to develop peptides for amyloid interaction, Fmoc-based solid phase peptide synthesis (SPPS) and combinatorial screening techniques have been utilized. The ability to harness the unpredictable molecular interaction of randomized peptides, to produce sequence specific binding partner is the promise of this methodology. The identified peptide hits were discovered to have a diverse composition. Detailed analysis by comprehensive on-beads binding studies revealed the strongest hits to be rather non-polar in nature, with binding constants in the nanomolar range. New reactions have also been developed for peptide chemistry on the HMBA linker. These include convenient methods for cleavage and simultaneous C-terminal functionalization of peptides, to form acids amides and esters. All reactions utilize the strong leaving group potential of the HMBA linker to facilitate nucleophilic attack. Generally esters were formed fast and efficiently using strong base and neat alcohol, with high purity of the target peptide esters. The tested amines were sufficiently nucleophilic to form the corresponding amides without activation. MIDA protected boryl aldehyde has been successfully used to synthesize linear and cyclic peptides containing a boronic acid peptoid functionality. The reductive amination of the boryl aldehyde with the N-terminus of peptides was effective on solid support and the MIDA group was determined to be stable towards peptide coupling conditions.
UR - https://rex.kb.dk/primo-explore/fulldisplay?docid=KGL01012014004&context=L&vid=NUI&search_scope=KGL&tab=default_tab&lang=da_DK
M3 - Ph.D. thesis
BT - Combinatorally Evolved Peptides: Targeting the Molecular Basis for Alzheimer's Disease
PB - Department of Chemistry, Faculty of Science, University of Copenhagen
ER -