Biomedical Engineering Reference
In-Depth Information
uncleaved sialic acid residues that may bind to viral hemagglutinin, causing viral aggregation and
thereby a reduction of the amount of virus that may infect other cells.
Thus, selective inhibitors of the enzyme neuraminidase are potential drugs against inl uenza.
The determination of a 3D structure of neuraminidase by x-ray crystallography in 1991 yielded a
breakthrough in the discovery of neuraminidase inhibitors being sialic acid analogous by biostructure-
based methods.
It was shown that neuraminidase forms a homotetramer and that each monomer contains 6 four-
stranded antiparallel beta-sheets arranged as blades on a propeller. The active site was identii ed
from complexes with inhibitors of the enzyme and is located in a deep cavity on the surface of the
enzyme (Figure 2.4). The active site is primarily formed by charged and polar residues, rel ecting
that the substrate is also a polar compound.
The mechanism for hydrolysis of glycoconjugates (Figure 2.5A) by neuraminidase yielding sialic
acid (Figure 2.5C) is proposed to proceed via a l at oxonium cation transition state (Figure 2.5B).
(A)
(B)
(C)
FIGURE 2.4
3D structure of inl uenza virus neuraminidase (pdb-code 2QWK). (A) Homotetramer shown
as ribbon representation. Four inhibitor molecules bound to the enzyme are shown as space-i lling models.
(B) Ribbon representation of one monomer colored continuously from blue (N-terminus) to red (C-terminus).
An inhibitor is shown as a stick model. (C) Surface representation of monomeric neuraminidase with an
inhibitor occupying the active site.
OH
HN
O
OH
HN
O
OH
HN
O
H
H
H
OH
OH
OH
HO
HO
HO
OH
O
OH
O
OH
O
+
RO
CO
2
H
HO
CO
2
H
O
O
-
(A)
(B)
(C)
O
OH
HN
HN
O
OH
N
H
H
OH
NH
HO
HO
O
O
OH
OH
NH
2
CO
2
H
CO
2
H
(D)
(E)
FIGURE 2.5
The biostructure-based design process leading to of zanamivir (Relenza): chemical structure of the
glycoconjugates (R = sugar) (A), the proposed transition state (B), sialic acid (C), DANA (D), and zanamivir (E).
