DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

HIV virus
membrane
1657
1
Nucleocapsid
core
gp 120 anchors
HIV to target cell
by binding to CD4.
CD4
HIV fusion
protein gp41
HIV envelope
protein gp120
Figure 59–7. Mechanism of action of the HIV entry inhibitor maraviroc.
2
CCR5 chemokine receptor binding stabilizes complex
and allows gp41-mediated fusion of virus membrane
with target cell membrane.
3
CCR5
N
N
N
Maraviroc
N
HN
Maraviroc binds to CCR5, preventing
gp120 binding, fusion, and entry.
O
F
F
CHAPTER 59
ANTIRETROVIRAL AGENTS AND TREATMENT OF HIV INFECTION
baseline. In addition, the requirement for an expensive baseline phenotype
test limits its cost effectiveness.
Enfuvirtide
Chemistry and Antiviral Activity. Enfuvirtide is a 36-amino-acid
synthetic peptide whose sequence is derived from a part of the transmembrane
gp41 region of HIV-1 that is involved in fusion of the
virus membrane lipid bilayer with that of the host cell membrane.
Enfuvirtide is not active against HIV-2 but has a broad range of
potencies against HIV-1 laboratory and clinical isolates. The reported
in vitro IC 50
ranges from 0.1 nM to 1.7 μM depending on the HIV-1
strain and testing method employed (Dando and Perry, 2003).
Enfuvirtide was investigated originally as a possible vaccine
component, in part because of a high degree of sequence conservation
among HIV-1 strains. This peptide turned out to have potent
anti-HIV activity in vitro, a property eventually attributed to selective
inhibition of HIV-mediated membrane fusion (Jiang et al., 1993;
Wild et al., 1994). Enfuvirtide is expensive to manufacture and must
be administered by subcutaneous injection twice daily. Thus cost
and route of administration limit its use to those with no other treatment
options.
Mechanisms of Action and Resistance. Enfuvirtide has a unique
mechanism of antiretroviral action. The peptide blocks the interaction
between the N36 and C34 sequences of the gp41 glycoprotein
by binding to a hydrophobic groove in the N36 coil. This prevents
formation of a six-helix bundle critical for membrane fusion and
viral entry into the host cell. Enfuvirtide inhibits infection of CD4+
cells by free virus particles, as well as cell-to-cell transmission of
HIV in vitro. Enfuvirtide retains activity against viruses that have
become resistant to antiretroviral agents of other classes because of
its unique mechanism of action.
HIV can develop resistance to this drug through specific mutations
in the enfuvirtide-binding domain of gp41. Of the patients experiencing
virologic failure during enfuvirtide treatment, 94% had virus
with mutations in the gp41 region associated with enfuvirtide resistance
in vitro. The most common mutations involve a V38A or N43D substitution.
Single-amino-acid substitutions can confer up to 450-fold resistance
in vitro, although high-level clinical resistance is usually associated
with two or more amino acid changes (Dando and Perry, 2003).
Absorption, Distribution, and Elimination. Enfuvirtide is the only
approved antiretroviral drug that must be administered parenterally.
The bioavailability of subcutaneous enfuvirtide is 84% compared