4th EucheMs chemistry congress

Poster Session 1
s889
chem. Listy 106, s587–s1425 (2012)
Poster session 1 - life sciences
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ConforMAtionAL StABiLity of A noveL
AMyLoid-BetA tetrAMer toPoLoGy
A. h. C. horn 1 , e. SoCher 1 , h. StiCht 1
1 Institute for Biochemistry, Medicine, Erlangen, Germany
The amyloid-β (Aβ) peptide is a key molecule in the
pathogenesis of Alzheimer’s disease (AD), the most common
neurodegenerative disorder. Originally, the Aβ fibrils were
postulated to be the neurotoxic agents for a long time, because an
increased presence of extracellular amyloid plaques, composed
primarily of insoluble Aβ fibrils, is found in the brain of affected
patients. Recent studies, however, showed a higher cytotoxicity
for small Aβ oligomers than for the Aβ fibrils so that these soluble
Aβ oligomers are moving to the centre of interest now.
Because of the unstable and noncrystalline nature of these
species, obtaining structural information for small oligomers is an
experimentally challenging task. Novel structural insight was
obtained from a recent crystal structure of a tetramer formed by
the amyloidogenic residues 18-41 of the Aβ peptide. To enhance
stability, this fragment was genetically engineered into the CDR3
loop region of a shark Ig single variable domain antibody.
Since the respective crystal structure is stabilized by the
antibody moiety, we investigated, whether the respective topology
also represents a stable fold for the isolated Aβ-peptide.
We performed molecular dynamics simulations (200ns) in
explicit solvent for the isolated tetrameric amyloid-β fragment in
two different lengths (17-40 or 17-42) and the derived dimer and
monomer structures.
In contrast to the tetramer of Aβ , we observed a stable
17-40
dynamical behaviour of Aβ : The extension of the antiparallel
17-42
β-sheet (through the residues 41 and 42) is responsible for the
enhanced structural stability in Aβ . 17-42
In summary, our results suggest that the novel tetrameric
structure represents a stable oligomer conformation for the longer
and more neurotoxic Aβ species and thus could be a new target
42
in rational drug design aiming at the prevention of toxic oligomer
formation.
Keywords: Amyloid beta-peptides; Molecular dynamics;
Protein structures; Aggregation; Medicinal chemistry;
4 th EucheMs chemistry congress
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the iMPACt of the BiSPidine StruCture on
the StABiLity of their Cu(ii) CoMPLexeS
S. hunoLdt 1 , P. CoMBA 2 , M. MorGAn 2 ,
J. SteinBACh 1 , h. StePhAn 1
1 Helmholtz-Zentrum Dresden-Rossendorf, Institut of
Radiopharmacy, Dresden, Germany
2 University of Heidelberg, Institut of Inorganic Chemistry,
Heidelberg, Germany
Rigid bispidine (3,7-diazabicyclo[3.3.1]nonane) derivatives
have been shown to form stable complexes, particularly with first
row transition metal ions. [1] The variable number, type and
position of donor groups provide a variety of tailor-made
coordination sites for specific metal ions. Furthermore, the
bispidine skeleton opens suitable pathways to introduce
biomolecules, which are important in view of the pharmaceutical
targeting of such complexes. Due to these interesting features,
bispidines are predestined as attractive bifunctional chelating
agents for the development of target-specific copper-based
radiopharmaceuticals. In this perspective, a hexadentate bispidine
ligand consisting of pyridine units in the positions C-2, C-4, N-3,
and N-7 was conjugated to the tumour-seeking peptide bombesin.
The 64Cu-labeled bioconjugate is accumulated in human prostate
tumors to allow clear visualization of the tumor tissue. [2]
In order to optimize the radiopharmaceutical behavior,
further bispidine ligands have been developed with different
denticity (tetra-, penta, hexadentate) with pyridine and/or
methoxypyridine donor groups and with the possibility to
introduce functionalities, such as targeting units and fluorescence
labels in view of pharmaceutical targeting as well as dual labeling
(PET and optical imaging).
These ligands and the important properties of their CuII complexes, e. g. stabilities, exchange kinetics and partition
coefficients ( 64Cu: octanol/water) will be reported.
references:
1. P. Comba, M. Kerscher, W. Schiek, Progr. Inorg. Chem.
2008, 55, 613-704.
2. S. Juran, M. Walther, H. Stephan, R. Bergmann,
J. Steinbach, W. Kraus, F. Emmerling, P. Comba,
Bioconjugate Chem. 2009, 20, 347-359.
Keywords: ligand design; imaging agents; copper;
AUGUst 26–30, 2012, PrAGUE, cZEcH rEPUbLIc