Protease inhibitors (PIs)

A clear understanding of the key sites of action for the newer
antiviral compounds in development is of outmost importance.
HCV is a positive-sense single-stranded RNA virus, meaning that
its genome can function directly as a template for viral protein
synthesis. Consequently, after entering into hepatocytes, HCV
starts its replication by direct translation of the genome into a
large polypeptide that is further processed by the virus NS3
protease. This enzyme has dual activity of serine protease and of
helicase (unwinding the single-strand viral RNA). Together with
the NS4A cofactor, the NS3 protease is responsible for
proteolytic cleavage of its downstream nonstructural proteins
that in turn are critical in forming the replicative complex from
which viral synthesis occurs. Additionally, NS3 protease may
directly impair host IFN responses through the inhibition of
phosphorylation of IFN regulatory factor-3, and administration
of PIs may restore interferon responsiveness.
66 | Hepatitis C Treatment
Both FDA-approved PIs – Telaprevir and Boceprevir – are
peptidomimetic PIs that bind reversibly and block the protease
catalytic site.
However, monotherapy with PIs is not an option, due to
early emergence of resistance. Minor resistant populations
preexist at baseline in all HCV-infected patients and are rapidly
selected with PIs monotherapy. Therefore, boceprevir and
telaprevir still require a platform of PegIFN/RBV. When
administered in this triple therapy combination, each of the two
PIs substantially increases the rates of SVR in both treatmentnaive
and treatment-experienced patients