sterol in fungi. Amphotericin B binds to cell membrane ergosterol in the fungi, and the
resulting drug–lipid complex produces leaks in the membrane that ultimately culminate
in death of the fungal cell. Approaches to the design of antifungal agents are described
in greater detail in section 9.5.
7.2.2 Targeting Biochemical Injuries to Cell Membrane LipidsAlthough it is difficult to target drugs against endogenous lipid molecules, it is much
easier to target pathological processes involving membrane lipids. Acute ischemic or
traumatic injury provides a good working example of such a design strategy. Ischemic
and traumatic injuries to the central nervous system are common causes of irreversible
damage to the brain and spinal cord. One of the leading molecular mechanisms for such
irreversible damage is via membrane lipid peroxidation.
Lipid peroxidation of cellular membrane components is a chain reaction that ulti-
mately destroys the polyunsaturated chains of membrane phospholipids. This process
occurs when a reactive oxygen species (e.g., superoxide anion, hydroxyl radical, per-
oxyl radical, hydrogen peroxide with iron) or a carbon radical attacks the fatty acid
chains of membrane phospholipids. A radical (sometimes called a “free radical”) is a
neutral chemical species that contains an odd number of electrons and thus has a single
unpaired electron in one of its orbitals. Radicals are highly reactive because they con-
tain an atom with an odd number of electrons (usually seven) in its valence shell, rather
than a stable noble gas octet. A radical can achieve a stable valence shell octet of elec-
trons through an abstraction process with another molecule, leaving behind a new rad-
ical. Such processes lead to reactions such as radical substitutions or radical additions.
Radical reactions normally require three steps: initiation, propagation, and termination.
During propagation, the radical reaction becomes a self-sustaining cycle, making the
overall process a chain reaction. The unsaturated fatty acids of the phospholipids of the
cell membrane are particularly susceptible to attack by radicals because of their allylic
hydrogens. Hydrogen abstraction initiates the chain reaction; the resulting allyl radical
product then abstracts hydrogens from adjacent chains or reacts with oxygen to form a
lipid peroxyl radical. This initial radical attack can be catalyzed by iron, which can
decompose lipid hydroperoxides to peroxyl and alkoxy radicals that in turn initiate new
lipid radical chain reactions. This cascade of chain reactions effectively attacks the cell
membrane.
The structural integrity of the cell membrane is irreversibly damaged by the process
of membrane lipid peroxidation. The damaged membrane becomes leaky and extra-
cellular calcium enters the cell. This in turn activates calcium-dependent phospholi-
pases and protein kinases, subsequently leading to fatty acid cleavage and other
biochemical alterations within the cell. Ultimately this leads to damage or death of
the cell.
The importance of cell death mediated by oxidative damage has led to the popularity
of antioxidants as potential therapeutics. A variety of naturally occurring (vitamin C,
vitamin E) and synthetic (lazaroids) antioxidants have been studied as possible reme-
dies for a wide variety of ailments. Large doses of vitamin E have been studied as a
putative therapy in Alzheimer’s disease, functioning through the inhibition of amyloid-
induced oxidative destruction of neuronal membranes within the brain.
ENDOGENOUS CELLULAR STRUCTURES 411