20-F-20-C-Methyl Nucleosides and Nucleotides for the Treatment of Hepatitis C Virus: from Discovery to the Clinic - Accounts in Drug Discovery Case Studies in Medicinal Chemistry - page 240

Although nucleosides possess many positive attributes, they have their own
challenges related to the discovery of therapeutically useful agents. For a
nucleoside analog, it is the triphosphate metabolite that is the pharmacologi-
cally active agent. The triphosphate is the substrate for the viral polymerase
ultimately incorporating the nucleoside monophosphate into the growing RNA
chain and effecting a chain termination event (Figure 11.1). Therefore, in order
for a nucleoside to be metabolized to the active 5 0 -triphosphate, it must be a
substrate for at least three different kinases and undergo three phosphorylation
steps. Consequently, for nucleosides it is di cult to predict if a particular
nucleoside will be active against a suspect viral target using standard medicinal
chemistry structure-activity relationship (SAR) principles, since any particular
nucleoside must be a substrate for at least three kinases and one polymerase,
thus potentially demonstrating competing SAR trends.

BASE

BASE

BASE

O

O

HO

O

Kinase 1 Kinase 2

X

X

X

HO Y

HO Y

HO

Y

HO

=Phosphate

Kinase 3 Y

O

X

BASE

Polymerase

5'

HO

Y
X

Chain
Termination

HO

HO HO HO HO

O O O O O O

Ade Ura Ade Ura Gua BASE

RNA

Gua Ura Ade Ura Ade Cyt

Ade

O O O O

O O O

OH OH OH OH OH

OH OH

3'

Figure 11.1

In order for a nucleoside to inhibit a viral polymerase, it must first
be phosphorylated to its active triphosphate derivative and then be
incorporated into the growing RNA chain to affect a chain termination
event.