Chemistry Reference
In-Depth Information
TAGSFREE for many different peptide dendrimer combinatorial libraries and thus
tested probably the largest number of dendrimers ever prepared by any method
so far. One of the most spectacular applications of the TAGSFREE design is a
390,625-member combinatorial library of glycopeptide dendrimers with variable
multivalency and variable branch length based on the silent encoding of amino
acid deletions made possible by the AAA, which lead to the identification of
dendrimer
cFuc
4
(LysArgLeu)
2
DapArgIlePheLeuNH
2
as a potent lectin ligand
(Figure 15.3) [21].
KT1
15.3 ENZYME MODELS
From the point of view of synthetic chemists, enzyme catalysis is one of the most
fascinating properties of natural proteins, which calls for the study of synthetic
models of enzymes [22]. Enzyme catalysis results from cooperativity between
different amino acids and cofactors within the protein. Considering that arranging
amino acids in a dendritic framework primarily enforces spatial proximity, peptide
dendrimers seem particularly well suited to investigate such cooperativity effects.
Within the SPPS combinatorial approach chosen for the assembly of peptide
dendrimers, investigating catalysis should be realized by library screening, which
is facilitated by numerous and efficient high-throughput assays available to
measure enzyme-catalyzed reactions [23]. Dendrimer libraries for catalysis are
designed to display amino acid residues with known catalytic properties for the
reaction under study.
Our work so far has concerned histidine-containing ester hydrolysis catalysts as
above, and amine-functionalized dendrimers that catalyze aldol reactions via en-
amine or enolate mechanisms.
10
We have also investigated peptide dendrimer models
of metalloproteins, namely peptide dendrimers that bind vitamin B
12
by coordination
at cobalt of a nucleophilic residue at the dendrimer core [24], and the binding of Fe(II)
to bipyridine-containing peptide dendrimers [25]. All of these systems operate in
aqueous environment under conditions that are typical for enzyme-catalyzed pro-
cesses. Catalytic and binding properties are governed by dendrimer size and the nature
and position of the amino acid residues within the branches. Results indicate that
multivalency, hydrophobic and electrostatic effects are key parameters influencing
binding and catalysis in these peptide dendrimers. Optimization of catalysis and
binding is possible by amino acid substitutions.
15.3.1 Dendritic Effects
Dendritic effects in catalysis are understood as a variation of catalytic efficiency as the
dendrimer size increases. In the first approach toward catalytic dendrimers, catalytic
groups are displayed in multiple copies at the dendrimer surface. Favorable
cooperative effects between these groups might enhance catalysis compared to a
monovalent or lower valency system. However, multivalency often also induces steric
crowding that can block substrate access and decrease catalytic efficiency [10a].
