Chemistry Reference
In-Depth Information
Glucosidase Inhibitors
The other class of chemotherapeutics involved in the viral adsorption acts by inhibiting glucosidase, which play a
role in glycoprotein biosynthesis.
Glucosidases are enzymes that catalyze the cleavage of glycosidic bonds by
processing of complex carbohydrates, fundamental in many cellular recognition processes, such as (i) cleavage of
diet polysaccharides in monosaccharide, which are metabolically absorbed and used by the organism, (ii) lysosomal
glycoconjugate catabolism and glycoprotein processing, and (iii) biosynthesis of oligosaccharides in glycoproteins
or glycolipids. Inhibition of these glucosidases can affect quality control, maturation, transport, secretion of
glycoproteins, and can alter cell-cell or cell-virus recognition processes [17, 15].
The enzymes glucosidase I and II are involved in key steps during the processing of
N
-linked oligosaccharides by
cleaving three terminal glucose residues from the tetradeca-oligosaccharide moiety Glc
3
Man
9
GlcNAc
2
of an
important
N
-linked oligosaccharide intermediate (Scheme
1
). Inhibitors of such enzymes affect the formation of
these oligosaccharides and have shown remarkable anti-HIV activity, which may lead to unsuccessful completion of
gp120 in the viral reproduction [18].
OH
OH
OH
HO
HO
HO
C
-
O
O
O
HO
O
O
O
(Man)
8
(GlcNAc)
2
Asn
Protein
O
OH
OH
OH
immature oligosaccharide
O
HO
OH
D
-glucosidase I and II
OH
OH
OH
HO
HO
O
O
3X
+
HO
OH
HO
O
(Man)
8
(GlcNAc)
2
Asn
Protein
OH
OH
Scheme 1:
Processing of
N
-linked oligosaccharides by the action of glucosidase I and II enzymes [15].
glucose
The functions of glucosidases in the organism justify the search for potential therapeutic inhibitors to be used in
diabetes, obesity, glycosphingolipid lysosomal storage disease, HIV infections, and tumors in general. Some drugs
are used as therapeutic agents can be exemplified by acarbose (
1
) (Precose®), miglitol (
2
) (Glyset®), and
N
-butyl-1-
deoxynojirimycin (
3
) (Zavesca®) (Fig.
5
). Drugs
1
and
2
are used in the treatment of non-insulin-dependent
diabetes, type II, interfering with the digestion of dietary carbohydrates, whilst drug
3
is employed for the control of
the metabolic Gaucher's disease [15].
OH
OH
OH
H
3
C
O
O
O
HO
N
H
O
O
OH
HO
OH
HO
OH
HO
OH
HO
OH
Acarbose (1)
HO
HO
OH
N
N
HO
HO
HO
OH
HO
OH
Miglitol (2)
N
-butyl-1-deoxynojirimycin (3)
Figure 5:
Examples of glucosidase inhibitors available in the therapeutic.
