Biology Reference
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d-amino acids (natural amino acids are in the l-configuration) are rela-
tively resistant to proteolysis. To find such peptides, a pentapeptide library
was synthesized from d-amino acids on a membrane. The library was
incubated with a radiolabeled peptide containing the KLVFF-motif and
several strong binders were found with a sequence similar to a “reversed”
KLVFF peptide, e.g. yfllr (d-amino acids are represented by lower case
letters). Similarly to KLVFF, the yfllr peptide inhibited A
fibril forma-
tion as observed by EM (Tjernberg
et al
., 1997). Proline is known to be
incompatible with
β
-sheets, and a pentapeptide with the sequence LPFFD
(compare with KLVFF) was found to inhibit fibril formation and to pre-
vent A
β
-induced neuronal death in cell culture (Soto
et al
., 1998).
Moreover, this peptide was found to block fibril formation in a rat brain
model of amyloidosis. A modified, endprotected variant of the peptide
was tested in transgenic mice overexpressing A
β
, showing a clear reduc-
tion in amyloid burden and decreased neuronal damage (Permanne
et al
.,
2002). In this study, the peptide was administered by intraperitoneal
injection or intra-cerebroventricular infusion, and further improvement
regarding proteolytic stability in order to allow intravenous or oral admin-
istration was necessary. This was achieved by methylation of one nitrogen
atom in the backbone of the peptide (Adessi
et al
., 2003). The modified
peptide showed good brain uptake, efficient inhibition of A
β
β
-polymeriza-
tion and protected cells from A
-induced toxicity. Thus, it is possible to
increase the stability of KLVFF-like peptides by different modifications
and use such peptides, or peptidomimetics, for lowering of the amyloid
burden and increasing neuronal survival in transgenic mice models of
amyloid.
It is likely that small organic molecules would be more stable and bet-
ter suited for pharmacological treatment of AD than peptide-derived mol-
ecules. Several different small organic molecules have been found to
affect A
β
-polymerization, but only a few have entered clinical trials. One
of these, 3-amino-1-propanesulfonic acid showed good results in animal
studies and eventually entered phase III clinical trials. Unfortunately, the
outcome of this trial was not positive and no clear effect on cognition
could be observed. Another organic compound under investigation is
β
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