Table 1 Functional targeting of the HCV replicase

NS2

At least one transmembrane domain

(1) NS2–NS3 proteolytic cleavage

(1) Transmembrane domains

No^a

Preclinical

(2) Protease active site

(3) Dimerization motif

NS3

None

(1) Serine protease domain releases NS proteins downstream

(1) Protease active site

Yes

Phase lll/IV^b

(2) Helicase active site

(2) Helicase domain unwinds dsRNA/ssRNA

(3) NTPase active site

(4) RNA-binding region

(5) NS4A- and NS5B-interaction regions

NS4A

N-terminal transmembrane domain

(1) NS3 cofactor for proper folding and membrane localization

(1) N-terminal transmembrane domain

Yes

ibid

NS4B

N-terminal AH

(1) Induces membranous web formation

(1) N-terminal AH

Yes

Phase I

(2) Internal AH

(3) RNA-binding region

(4) Oligomerization motif

NS5A

N-terminal AH

Unknown^c

(1) N-terminal AH

Yes

Phase I^d

(2) Domain I dimerization motif for RNA binding

(3) Core protein interaction region

NS5B

C-terminal anchor region

(1) Synthesis of viral genome RNA

(1) Polymerase active site

Yes

Phase II

(2) Allosteric binding sites

(3) NS3- and NS5A-interaction regions

(4) RNA-binding region

(5) Oligomerization motif