Biology Reference
In-Depth Information
For HIV, most marketed drugs for treating AIDS are inhibitors of HIV-1
reverse transcriptase or protease enzymes, but new targets include the integrase
enzyme, cell-surface interactions, membrane fusion, and also virus particle
maturation and assembly (Kaushik-Basu
., 2008). Entry inhibition entails
preventing HIV-1 breaching the cell, either as a strategy to prevent infection
altogether or to curtail infection of new cells in an HIV-positive individual.
Several strategies have proved effective in HIV-1 entry inhibition either
et al
in vitro
(using pseudoparticles or replication competent viruses) or
: binding to
viral surface proteins gp120 and gp41, binding to human cell surface receptor
CD4, and binding to human cell surface coreceptors, CCR5 and CXCR4
(Leonard and Roy, 2006; Liu
in vivo
., 2007). In particular, the synthesized peptide
T-20 is believed to act by binding to gp41 (Wild
et al
., 1993, 1994) and is
currently in clinical use. Yet, several more recent studies have revealed that T-20
does not block the six-helix bundle prehairpin formation (Liu
et al
., 2005).
Another peptide, C37, derived from the C-terminus of gp41 (and nearly identi-
cal to the widely reported C-peptide C34; Liu
et al
., 2001), is
also described as having strong anti-HIV entry activity due to the tight binding
of the gp41 N-terminal helices. Maraviroc is a small antiretroviral compound
known to be a CCR5 antagonist, which blocks R5-tropic HIV entry into CD4
cells (Hunt and Romanelli, 2009). Several studies have established that synergy
can occasionally be observed when two fusion inhibitors are combined in a viral
assay or
et al
., 2005; Root
et al
fusion assay. For example, some synergy is observed in the
combination of CCR5 antibodies with T-20 (Ji
in vitro
., 2006),
the combination of small molecular antagonists of coreceptors with T-20
(Tremblay
et al
., 2007; Murga
et al
., 2000, 2002), the combination of small molecular antagonists
of CCR5 with CCR5 antibodies (Ji
et al
., 2006), and the
combination of small molecular antagonists of CCR5 with chemokines (Murga
et al
et al
., 2007; Murga
et al
., 2002).
In the case of HCV, entry into hepatocytes is a multistep process,
involving at least four cellular receptors, leading to virion endocytosis and fusion
of the viral and cellular membranes. Unlike the HCV replication process, these
steps have not been thoroughly exploited as targets for antiviral intervention.
Recently, with the development of HCVpp and the JFH1 infectious molecular
clone, it has become possible to test drugs against entry.
., 2006; Tremblay
et al
, proof-of-concept
studies for inhibiting the HCV entry process have been demonstrated using
cyanovirin-N that targets the N-linked glycans of the viral envelope proteins
and prevents E2-CD81 interaction (Helle
In vitro
., 2006), neutralizing antibodies
directed against the HCV E1 and E2 proteins (Broering
et al
et al
., 2009; Habersetzer
et al
., 1998; Keck
et al
., 2008; Law
et al
., 2008; Owsianka
et al
., 2005; Perotti
et al
.,
2008; Schofield
et al
., 2005; Yu
et al
., 2004), antibodies against cellular receptors
CD81 (Bartosch
et al
., 2003; Cormier
et al
., 2004; Lavillette
et al
., 2005; Molina
et al
., 2008), SR-BI (Catanese
et al
., 2007; Zeisel
et al
., 2007), Claudin-1
