Nucleic Acids in Chemistry and Biology

because the nucleoside is a substrate for the viral thymidine kinasebut not for the host-cell TK. This viral
thymidine kinase is also a thymidylate kinase and produces the BVDU 5-diphosphate, but only in HSV-1
infected cells because diphosphate formation does not occur efficiently with the HSV-2 encoded enzyme.
BVDU is a substrate for nucleoside phosphorylase but it sufficiently avoids degradation to show useful
clinical activity. The base (E)-5-(2-bromovinyl)uracil is an inhibitor for pyrimidine-5,6-dihydroreductase,
the first enzyme in pyrimidine catabolism and thus can actually be salvaged and the 2-deoxyribonucleoside
can be regenerated. BVDU triphosphate is an inhibitor of the virally encoded DNA polymerase. A nucle-
oside phosphorylase-resistant analogue of BVDU (Figure 3.95d) has been described which has substan-
tially greater activity in vivo because it has a much longer half-life in serum. The carbocyclic analogue of
BVDU (Figure 3.95e) also has significant activity.

3.7.2.2.4 Ribavirin. The broad spectrum anti-viral activity of ribavirin(1-
-D-ribofuranosyl-1,2,4-

triazole-3-carboxamide; Figure 3.96) was first described in 1972.^137 Since then, it has been studied in more
animals and against more viruses than any other anti-viral agent. It is also apparently active in cell culture
against about 85% of all virus species studied and shows little or no cellular toxicity. Until recently its main
clinical use in the USA was in aerosol form against respiratory syncytial virus in young children. Very recently
it has been approved as a combination treatment against chronic hepatitis C infections. It is also known to
be effective against Lassa fever and influenza and its potential for the treatment of severe acute respiratory
syndrome (SARS) is currently under investigation.
The mode of action of ribavirin is somewhat controversial. The most abundant form of ribavirin in
cells is the triphosphate (Figure 3.96) and this was originally thought to inhibit inosine monophosphate

Nucleosides and Nucleotides 135

X

HO

HO

O

N

NH

R O

H

H H

H

H Br

H

H Br

H

H Br

(a) R = I, X = O

(b) R = X = O

(c) R = X = O

(d) R = X = S

(e) R = X = CH 2

Figure 3.95 Anti-viral pyrimidine 5-substituted 2-deoxyuridines

O

HO

HO

OH

NN

N

O

NH 2

O

P

O

P

O

P

O

OOOOO O

O

HO OH

NN

N CONH

2

Figure 3.96 Ribavirin (left) and its triphosphate (right)

O

Ade

CH 3

OP

O

O O

O

O O O

O

O

Ade

OP

O

t-Bu O

O

t-Bu O O

O

O

Cyt

HOP

O

HO

OH

O

Ade

P

HO

O

HO

OH

HPMPA tenofovir disoproxil adefovir dipivoxil cidofovir

Figure 3.94 Structures of acyclonucleoside phosphonates used as anti-viral agents