Cell Entry of Enveloped Viruses - Advances in Genetics - page 147

viruses contain this short JMD region in the ectodomain between the end of
HR-2 and the beginning of the transmembrane (TM) domain (Salzwedel ,

1999). The class II (SFV, dengue, TEBV) and class III (VSV and the herpes
virus) fusion proteins also possess these regions, although they are less rich in
tryptophan than the class I JMD (Jeetendra

et al.

., 2008).
Although the JMDs of fusion proteins of enveloped viruses are rich in aromatic
amino acids, the number, spacing, and sequence of the aromatic amino acids are
quite variable; however, the function remains the same. These JMDs contribute
to the conformational changes that occur during membrane fusion, interact with
membranes, induce membrane destabilization, and/or facilitate membrane fusion
(Munoz-Barroso

et al ., 2002, 2003; Roche et al

., 1999). Therefore, the JMD of viral fusion proteins is a
potential target for viral inhibitors. Entry inhibitors that target the JMD of class I
fusion proteins include monoclonal antibodies that bind the JMD of gp41 to the
FIV and to the HIV (Lorizate

et al

, 1994). Some peptides
that mimic the JMD have been designed for EnvGP of FIV (Giannecchini

et al. , 2006; Purtscher et al.

et al. ,

2004), HIV (Moreno et al. , 2006), Ebola virus (Saez-Cirion et al ., 2003), and the

SARS virus (Howard , 2008) and inhibit viral entry. This strategy has been

also broadly used against many other paramyxoviruses such as the Sendai virus
(Joshi

et al.

et al. , 1998; Rapaport et al. , 1995), the Newcastle disease virus (Young

et al. , 1999), the human parainfluenza type 3 (HPIV-3) (Yao and Compans,

1996), the respiratory syncytial virus (RSV), and the measles virus (MV)
(Lambert

, 1996). In the same way, peptides that mimic the JMD from
class II and III fusion proteins have also been developed against infection by
Dengue virus (Hrobowski

et al.

., 2006; Lopper and
Compton, 2004). In the case of HCV, some juxtamembrane domains have been
proposed in E1 and E2 (Drummer and Poumbourios, 2004; Drummer

et al. , 2005) and CMV (English et al

., 2007).
High-throughput screening (HTS) of peptides derived from E1 and E2 sequences
has identified inhibitory peptides close to the transmembrane domain of E2,
though they are not among the most inhibitory (Cheng

et al

, 2008). However,
these strategies suffer from certain limitations. The derived peptides of these
JMD often have the capacity to oligomerize, which inactivates them, and some
stratagems need to be implemented to make the peptides more bioreactive
against viruses. Moreover, these peptides that prevent the correct conformation-
al change of the envelope glycoprotein, must act in a certain window of time and
in a particular compartment compatible with their active structure. Indeed, the
acid pH of some compartment is not compatible with the bioactive structure of
the peptide. For the SARS-CoV virus, the peptide is able to inhibit the entry of
the virus in the presence of protease at the cellular surface, but the peptide has
little effect on the entry of the virus by endocytosis or on the activation by
cathepsin L in the acid conditions of the endosome (Ujike

et al.

In the
case of Influenza, it has not been possible to develop such inhibitory peptides
targeting the juxtamembrane domain. Reasons suggested for this include the

et al. , 2008) .