Chemistry Reference
In-Depth Information
NH
2
HO
HO
O
HO
OH
O
N
HO
N
OH
HN
HN
O
O
O
O
O
O
O
N
HN
NH
2
HN
N
O
O
H
2
N
HN
H
O
O
O
O
NH
N
O
O
NH
H
NH
NH
H
NH
O
O
O
N
H
O
N
O
O
O
NH
NH
2
O
HN
O
H
N
NH
N
H
2
N
NH
2
O
NH
O
O
OH
NH
O
N
O
H
2
N
OH
OH
OH
FD2
HO
OH
IC
50
(ELLA)
11
µ
M
0.14
Lectin
UEA-I
LecB
µ
M
FIGURE 15.8
Fucosyl peptide dendrimer
FD2
(cFucLysProLeu)
4
(LysPheLysIle)
2
LysHisI-
leNH
2
is a potent inhibitor of fucose-specific lectins UEA-I and LecB.
staining. The ELLAwas used to confirm the activity of positive hits from the on-bead
screening, and to carry out more detailed SAR studies, in particular regarding a
possible dendritic effect on binding. Thus, fragments of the most potent dendrimer
FD2
(cFucLysProLeu)
4
(LysPheLysIle)
2
LysHisIleNH
2
consisting of only the outer
branches, such as
2G1
(cFuc-LysProLeu)
2
LysPheLysIleNH
2
, showed much weaker
binding than
itself. Increasing multivalency from tetravalent to octavalent by
redesigning the sequence of
FD2
(cFucLysPro)
8
(LysLeuPhe)
4
(LysLysIle)
2
LysHisIleNH
2
, which showed an even stronger binding to lecB
(IC
50
¼
FD2
gave dendrimer
2G3
25 nM) [43].
15.4.3 Inhibition of P. aeruginosa Biofilms
P. aeruginosa causes lethal lung infections in immunocompromised patients and
those suffering from cystic fibrosis or cancer. Tissue attachment and the formation of
biofilms are essential steps in the process that also increase the antibiotic resistance of
the pathogen [44]. The glycopeptide dendrimer
FD2
and several analogs inhibit
biofilm formation and efficiently disperse established biofilms in cultures of several
P. aeruginosa strains including antibiotic-resistant isolates (Figure 15.9) [45]. The
effect is not mediated by cytotoxicity since bacterial growth is unaffected by the
ligands. Control experiments with lecB-deletion mutants and dendrimers that are not
ligands of lectin B show that biofilm inhibition requires both a potent ligand and lectin
B expression, suggesting that the effect is indeed caused by binding of the ligand to the
