prion protein is predominantly in an α-helical conformation, it is nontoxic; when it is
predominantly in a β-sheet conformation, it kills neurons. The prion protein is thus
made neurotoxic not by its amino acid composition but by its conformation. Prion dis-
eases are transmissible; thus prions are infectious agents. However, prions are not like
viruses, or other infectious microbes—prions are simply protein molecules; they are not
microbes with cell membranes and nucleic acids. Indeed, prions are not even infectious
molecules—they are infectious molecular shapes.
Like any other protein, the molecular structure of the prion is subject to conforma-
tional flexibility and to various thermal-induced fluctuations between varying confor-
mational states. However, if these fluctuations permit the PrPSCconformation to be
attained, then this abnormal conformer promotes the widespread conversion of PrPCto
PrPSC, leading to the precipitous deposition of the abnormal protein throughout the
brain (mirrored by the rapid and relentlessly downhill clinical course). This patholog-
ical self-propagating shape conversion of α-helical PrPCtoβ-sheet PrPSCmay in prin-
ciple be initiated by a “seed” PrPSCmolecule in the neurotoxic conformation. This
explains the transmissibility of prion diseases and accounts for how susceptible humans
exposed to beef from an animal with mad cow disease develop variant Creutzfeldt–
Jakob disease.
The concept of abnormal proteins in CJD may provide insights useful for drug
design. The pioneering work of Prusiner has enabled the preliminary identification of
prototype agents as therapies for CJD. Preliminary work identified two classes of com-
pounds with therapeutic potential: polysulphated molecules and tricyclic molecules
(e.g., phenothiazines, aminoacridines). These compounds bind to PrP and endeavor to
inhibit the PrPCto PrPSCcascade of conformational change.
Since prions affect cattle, elk, and other ruminant animals, it may be necessary to
design therapies for veterinary applications. However, designing drugs with a veteri-
nary application in cattle is different from designing drugs for domestic pets such as
cats or dogs. Cattle are an integral part of the human food chain. Drugs administered to
cattle have the potential to be consumed by humans. Under such circumstances, a drug
administered to cattle and consumed by humans could become an exogenous chemical
pathogen, conceivably causing health care concerns for the human. Arguably, other
therapies such as vaccines may have to be considered for the mass treatment of animals
susceptible to prion diseases.
9.3 Drug Design Targeting Viruses
Viruses are on the borderline between inanimate and living matter—one step above
prions, but one step below bacteria. Viruses can be crystallized, and the virus particle
shows a high degree of structural symmetry; alternatively, viruses can be cultured and
grown. Viruses are small (20–300 nm in diameter), containing a molecule of nucleic
acid as their genome. The nucleic acid is encased in a protein shell, termed a capsid,
which is itself composed of protein building blocks, or capsomeres. Some viruses have
a further membrane-like envelope around the capsomere. A number of viruses have this
envelope (pox, herpes, rhabdo, paramyxo, orthomyxo, toga); others do not (papova,
adeno, parvo, picorna). The entire infectious viral unit is called a virionand is shown
schematically in figure 9.1.
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