Biomedical Engineering Reference
In-Depth Information
CD4 binding site in
gp120: highly conserved,
target of neutral antibodies
Coreceptor binding site—
highly conserved. Target for
antibodies? Small molecule
inhibitors?
Helical domains—
targets for T20, small
molecules, and
antibodies
gp120
gp41
CD4
V3
Coreceptor
Coreceptor binding—target
for small molecule inhibitors:
CXCR4:
ALX40-4C
T22
AMD3100
CCR5:
TAK779
T20
FIGURE 24.9
Targets of opportunity: inhibition of HIV-1 entry. Binding of CD4 to gp 120 leads to exposure
of the highly conserved coreceptor binding site in gp 120. This domain and the CD4 binding region in gp 120
are potential targets for neutralizing antibodies. Binding of gp 120 to coreceptor can be inhibited by a variety
of small-molecule inhibitors, four of which have been described to date. Coreceptor binding is believed to
trigger additional conformational changes in gp41 including the formation of a triple-stranded coiled-coil with
insertion of the fusion peptide into the cell membrane. The transition from the triple-stranded coiled-coil to
the six helix bundle conformation is the proximal cause of membrane fusion and can be inhibited by T20. T20
is a peptide based on the second helical domain of gp41 that, by binding to the i rst helical domain, blocks
formation of the six helix bundle. (After Doms, R.W.,
Virology
, 276, 229, 2000.)
O
O
CH
3
HN
N
NH
2
HN
N
O
N
N
H
2
N
N
N
N
CH
2
N
OH
O
HO
O
(CH
3
)
3
C
C
C
O
O
CH
2
O
O
O
P
O
(CH
3
)
3
C
CH
2
OH
OH
O
Adefovir dipivoxil
Entecavir
Telbivudine
FIGURE 24.10
Structures of three antihepatitis B virus (anti-HBV) compounds.
Mechanism of action
: Serves as oral prodrug of adefovir (PMEA) that is targeted at HBV RT (and
HIV RT), and acts as a chain terminator, following intracellular phosphorylation to the diphosphate
form, and incorporation at the 3
-end of the viral DNA chain (Figure 24.3).
Principal indication(s)
: Chronic HBV infection, where it has proven successful in the treatment of both
HBeAg-positive and HBeAg-negative patients whether resistant to lamivudine or not.
Administered
: Orally as a single dose of 10 mg/day.
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