Biomedical Engineering Reference
In-Depth Information
Activity spectrum
: HSV-1, HSV-2, and VZV.
Mechanism of action
: Inhibits conversion of dUMP to dTMP by thymidylate synthase, following
intracellular phosphorylation to TFT 5
′
-monophosphate.
Principal indication(s)
: HSV keratitis.
Administered
: Topically as eyedrops (1%) or ophthalmic cream.
24.4.1.7 Brivudin
Structure
(Figure 24.11): (
E
)-5-(2-Bromovinyl)-2
′
-deoxyuridine, bromovinyldeoxyuridine (BVDU),
Zostex
®
, Brivirac
®
, Zerpex
®
.
Activity spectrum
: HSV (type 1), VZV, and some other (veterinarily important) herpesviruses.
Mechanism of action
: Targeted at the viral DNA polymerase, can act as competitive inhibitor (with
respect to the normal substrate, dTTP) after intracellular phosphorylation to BVDU 5
-triphosphate;
can also act as alternate substrate and be incorporated into the viral DNA, thus leading to a reduced
integrity and functioning of the viral DNA (Figure 24.13). The i rst and second phosphorylation
steps are catalyzed by the virus-encoded TK (HSV-1 TK, VZV TK), which explains the remarkable
specii city of BVDU for these viruses.
Principal indication(s)
: HSV-1 and VZV infections, particularly herpes zoster, but also HSV-1
keratitis and herpes labialis. Brivudin has been licensed for the treatment of herpes zoster in immu-
nocompetent patients in a number of European countries.
Administered
: Orally at 125 mg/day, once-daily (herpes zoster); can also be administered topically,
as 0.1%-0.5% eyedrops (herpetic keratitis) or 5% cream (herpes labialis).
′
O
O
O
O
Br
Br
Br
Br
HN
HN
HN
HN
O
O
O
O
N
N
N
N
O
O
O
O
P
P
HO
P
O
P
P
O
P
O
HSV-1 TK
VZV TK
HSV-1 TK
NDP kinase
OH
OH
OH
OH
BVDU-TP
VZV TK
BVDU
BVDU-MP
BVDU-DP
Viral DNA polymerase
DNA product
DNA template
FIGURE 24.13
Mechanism of antiviral action of BVDU. Following uptake by the (virus-infected) cells,
BVDU is phosphorylated by the virus-encoded thymidine kinase (TK) to the 5
-monophosphate (BVDU-MP)
and 5′-diphosphate (BVDU-DP), and further onto the 5′-triphosphate (BVDU-TP) by cellular kinases, i.e.,
nucleoside 5′-diphosphate (NDP) kinase. BVDU-TP can act as a competitive inhibitor/alternative substrate of
the viral DNA polymerase, and as a substrate it can be incorporated internally (via internucleotide linkages)
into the (growing) DNA chain. (After De Clercq, E.,
Biochem. Pharmacol
., 68, 2301, 2004a.)
′
