Chemistry Reference
In-Depth Information
Influenza virus (
Myxovirus influenzae
) belongs to the orthomyxoviridae family, which is subdivided into three
serologically distinct types: A, B and C. Only influenza virus A and B are of most concern in the human population,
with type A considered to be the most likely to cause pandemics. Further classification of influenza virus A is based
on the antigenic properties of its surface glycoproteins haemagglutinin (HA) and neuraminidase (NA), which are
essential for viral replication, infectivity and the infective cycle of influenza. These glycoproteins are able to
recognize the sialic acid
N
-acetylneuraminic acid (Neu5Ac); HA is a lectin that mediates the first contact between
the virus and the target host cell through recognition of sialic acid (SA) residues of cell-surface glycoconjugates,
while NA is an enzyme that catalyzes the removal of terminal SA linked to glycoproteins and glycolipids, which
enables the virus to infect different cells [20, 22].
Neuraminidase plays two critical roles in the life cycle of the virus, including virion progeny release and general
mobility of the virus in the respiratory tract. At molecular level, NA promotes the cleavage of the glycosidic bond of
glycoproteins and glycolipids, with release of terminal Neu5Ac residues. The enzymatic mechanism involves the
formation of a sialosyl cation intermediate (
5
) that adopts a distorted half-chair arrangement. A water molecule then
reacts in a stereoselective manner with the sialosyl cation intermediate to afford α-Neu5Ac (
6
) as the first product of
release, which then mutarotates to the thermodynamically more favourable β-anomer (
7
) (Scheme
2
) [22, 23].
Asp151
Tyr406
Asp151
B
Tyr406
Asp151
H
B
O
Tyr406
H
OH
B
O
HO
CO
2
H
OH
OH
O
O
O
R
HO
HO
AcHN
CO
2
HO
O
O
HO
CO
2
R
AcHN
AcHN
H
HO
R
Neu5Ac
R= protein or lipid
HO
HO
HO
HO
B
O
B
H
Glu277
Glu277
B
Sialosyl cation (5)
Glu277
Asp151
Asp151
OH
HO
CO
2
Tyr406
Tyr406
B
B
OH
O
AcHN
H
OH
H
O
HO
OH
HO
O
HO
HO
CO
2
O
-Neu5Ac (
6
)
O
CO
2
AcHN
AcHN
O
H
HO
HO
HO
HO
O
H
H
B
H
B
Glu277
Glu277
OH
Sialosyl cation (5)
Glycosyl-enzyme
intermediate
OH
HO
O
CO
2
AcHN
HO
HO
-Neu5Ac (
7
)
Scheme 2:
Enzymatic mechanism of influenza virus neuraminidase.
One of the first inhibitors of neuraminidase was the unsaturated Neu5Ac derivative 2-deoxy-2,3-didehydro-
N
-
acetylneuraminic acid (DANA) (
8
) (Fig.
7
), that is an analog of the transition state with a double bond between C-2
and C-3, which makes the ring planar, resembling the sialosyl cation (
5
). The inhibitor DANA (
8
) show a
micromolar order inhibition constant (K
i
= 10
-5
to 10
-6
M) but did not show selectivity for the viral sialidase
inhibition and failed in animal models infected with influenza virus. As DANA (
8
), the other designed inhibitors that
displayed inhibitory activity contain a double bond in the ring between C-2 and C-3, a carboxylate group at C-2, a
positively charged group (in physiological conditions) at C-4 and an
N
- acetamide group at C-5. This is related to
the trihydroxylated chain (C7-C9) present in compound (
8
), which can be substituted by a hydrophobic and
branching group (Fig.
7
) [23].
