Biomedical Engineering Reference
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OH
NH 2
OH
O
O
NH 2
3
O
O
HO
HO
O
O
O
O
HO
HO
Cl
Cl
HO
HO
O
O
O
O
Cl
Cl
HO
OH
HO
OH
O
O
O
O
O
O
N
N
N
N
N H 2
N H 2
O
H
N
O
H
N
N
N
H
H
O
H
H
H
H
O
O
O
O
O
N
N
O
O
H
H
O
H 2 N
O
H 2 N
OH
OH
OH
OH
O
O
HO
H
O
HO
O
N
O
R
H
O
R
H
O
O
O
1
2
Fig. 1 Comparison of interactions between Vancomycin (3) with normal (1) and mutated (2)
bacterial cell wall-forming peptide sequence. An attractive hydrogen bond is replaced for a
repulsive electrostatic interaction, thus decreasing the affinity of the antibiotic by a factor of 1,000
4
6
OH
O
OH
O
OH
H 2 N
O
NH
O
O
H
N
AA 1
AA 2
AA 3
O
H 2 NOC
N
NH 2
O
L-Disc
N
N
N
O
O
O
H
+
H
N
H
N
H
O
O
H
NH 2
N
N
H
N
H
O
O
+
O
O
H 2 N
OH
-
O
O
O
H
N
H 2 N
O
NH
N
H
O
OH
O
O
N
H
L-Tpi
H
N
8
O
5
7
AA 1-3 = L/D: Arg, Asn, His, Leu, N-Me-Leu, Lys, Phe, N-Me-Phe, Pro, Thr, Trp, Tyr, Tic
L: Aib, Chg, Atc, Dapa, Disc, Isn, Tpi, N-Me-Gly
34 × 34 × 34 = 39,304 receptors
Fig. 2 Schematic representation of receptor library 4 for the substrate N , N 0 -Ac 2 - L -Lys- D -Ala- D -
Lac-OH (5) ( left ) and receptor of highest affinity 8 with the amino acid sequence L -N-Me-Phe- L -
Disc- L -Tyr ( right )
of Vancomycin: the right part corresponding to a simplified carboxylate binding
pocket, which should be able to bind to both D -Ala-OH and D -Lac-OH via three
hydrogen bonds. The left side of the receptor, on the other hand, consists of a variable
tripeptide, which is free to rotate and should therefore be able to avoid electrostatic
repulsion between the antibiotic's carbonyl group and the lactate oxygen. Indeed, an
on-bead screening with a fluorescently labeled substrate revealed binding constants
five times as high as for Vancomycin. The best receptors mainly contained the amino
acid sequence L -Tpi- L -His (29%) and L -N-Me-Phe- L -Disc (20%) in position AA 1 and
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