Biomedical Engineering Reference
In-Depth Information
(A)
(B)
(C)
FIGURE 38.1 Generating a CovX-Body. (A) A payload functionalized with a specially designed
linker is synthesized. The linker is designed to be recognized and covalently bind only to the active
site of the antibody. (B) In a well-controlled reaction, the payload-linker is combined with CovX's
proprietary antibody. (C) The antibody selectively recognizes and combines with the linker, to form
a well-characterized, bivalent fusion molecule referred to as a CovX-Body. The fully assembled
CovX-Body is isolated by simple purification.
Immunization with such haptens resulted in antibodies that
catalyzed the target reactions by stabilizing the transition state
intermediates. The Scripps researchers reasoned that by using
reactive compounds as haptens they would be able to isolate
antibodies wherein the interaction with the antigen would
involve chemical reactivity in addition to nonpolar and electro-
static interactions. Antibodies identified from reactive immu-
nization were expected to behave more like enzymes, wherein
the active site amino acids participate in bond breaking and
bond forming reactions. The strategy of reactive immunization
was applied to identify antibody catalysts that would mimic
class I aldolase enzymes. Class I aldolase enzymes have an
active site Lysine residue whose
-amino group reacts with a
carbonyl group of the substrate to form a Schiff's base. The
Schiff's base serves as an electron sink that facilitates
the abstraction of H
รพ
from the C-
a
position resulting in the
formation of an enamine, thus activating the substrate as an
aldol donor (Figure 38.2). Asimple phenethyl-1,3-diketone (1)
e
(A)
O
H
+
H
-H
2
O
N
Lys
Enz
HN
Lys Enz
H
2
N
Lys Enz
HO
N
Lys Enz
B
Activated aidol
donor
H
(B)
O
HO
O
O
NH Lys Ab
H
2
N
Lys Ab
R
R
1
Lys
H
Lys
O
HN
Ab
Ab
O
N
Vinylogous
amide
B
H
H
R
R
Lys
Ab
OH
N
R
FIGURE 38.2 (A) Reaction mechanism of class I aldolase. (B) 1,3-diketone designed to trap lyinse
e
-amino group in the active site of the catalytic antibody and facilitate the formation of enamine
intermediate, analogous to the natural class I aldolase enzyme.
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