Molecular Recognition of Oligopeptides and Protein Surfaces - Designing Receptors for the Next Generation of Biosensors - page 72

N

AA 1 AA 2 AA 3 NHAc

O O O O

S

S

14

BocHN N

H

NH

O

dye

21

AA 1-3 =

template

Gly, L/D: Ala ,Val,
Leu, Phe, Pro, Ser,
Thr, Asp, Glu, Asn,
Gln, His, Lys, Arg

O

N

BocHN

NH

S S

O O O O

29 × 29 × 29 = 24,389 substrates

NH 2

O

O

NH 2

HO

O O

NH 2

N

HO HO

O

O

NH 2

NH 2

NH 2

22 23 24

NH 2

O

NH 2

HO O

O

NH
NH

N

O

HO

HO

NH 2

25 26 27

NH 2

Fig. 7 Schematic representation of tweezer receptors 21 and templates 22-27

able to achieve effective binding, the corresponding host systems with only two
amino acids per side chain and one-armed analogs were screened with the same
substrate library. However, as a result of truncation the host system completely lost
its binding affinity.
Under the conditions used for the experiments 15 seems to be the minimum
structure which is necessary for the recognition of the tripeptides under investigation.
In order to evaluate the role of the template on the binding properties, similar
receptors with the same side chains, but different diamine templates, 16-20,were
synthesized as well [ 18 ]. A screening against the same substrate library revealed that
with only a few exceptions these analogs do not bind to the substrates at all. The
U-shaped geometry of the original trans - trans -diketopiperazine template in 15
highly preorganizes the two arms in a fashion which is suitable for tripeptide binding.
On the other hand, side chains which are connected via the cis - cis -diastereomer 20
adopt an almost linear geometry. Hence, a defined angle between template and side
chains as well as a distance of approximately 8 ˚ in between (as is the case for the
original diketopiperazine scaffold) seems to be superior to all other templates that
were tested in this work. Accordingly, the template plays a decisive role in determin-
ing the affinity between receptor and substrate and thus has to be carefully chosen.
However, with the help of these host systems only rather moderate affinities could be
achieved. Although the selectivity is quite good, it has to be noted that the binding
studies were only carried out in organic solvent and not in water.
Further studies concerning the role of the template for the performance of
tweezer receptors were conducted by Liskamp [ 19 ]. As shown in Fig. 7 , the