Biology Reference
In-Depth Information
HO
O
O
O
(HO)
2
OPO
O
HO
O
NH
O
OPO(OH)
2
NH
O
O
HO
HO
HO
O
O
HO
O
HO
HO
OPO(OH)
2
O
NH
O
HO
HO
lipid IVa (
14
)
Lipid X (
15
)
Fig. 6.6 Some lipid A antagonists that act through the TLR4/CD14 receptor.
An early derivative, E-5531 (
12
), has been replaced by the easier-to-
synthesize, more robust, and more potent E-5564 (
13
) (also known as
Eritoran) (Qureshi
et al.
, 1991, Chilman-Blair
et al.
, 2003). Biosynthetic
lipid A precursor lipid Ia (
2
, see Fig. 6.1), and to a lesser extent Lipid X
(
14
), also are antagonists. Several other small molecules have also been
reported to inhibit TNFα production and to antagonize LPS activity by
targeting biological targets downstream from the LPS receptor(s).
Numerous small molecules target the natural inhibitor of NF-κB,
iκB. Abolishing the action of NF-κB effectively shuts down the lipid
A/TNFα cascade by interrupting intracellular signal transduction. Some
of these chemical agents, such as herbimycin A (
15
) and okadaic acid
(
16
), act by inhibiting iκB's phosphorylation (Fig. 6.7). The statins, a
family of natural and unnatural compounds used to lower cholesterol and
low-density lipoprotein (LDL) levels, inhibit the induction of pro-
inflammatory cytokines, also through blocking iκB's phosphorylation. In
particular, lovastatin (
17
) inhibits the production of TNFα, IL-1, and IL-
