Like any other protein, the molecular structure of the prion is subject to conformational
flexibility and to various thermal-induced fluctuations between varying conformational
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 pathological self-propagating
shape conversion of α-helical PrPCtoβ-sheet PrPSCmay in principle 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 (and Nobel Prize winning) work of Prusiner has enabled the preliminary
identification of prototype agents as therapies for CJD. Preliminary work identified two
classes of compounds 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.
8.3.1.2 Protein Folding Diseases: Alzheimer’s Dementia
Alzheimer’s disease (AD) is the most common neurodegenerative disease, affecting
2.2 million North Americans. Clinically, AD is characterized by a slowly progressive
dementia in which loss of short-term memory is a frequent early manifestation.
Pathologically, AD is characterized by the presence of two lesions: the plaque, which
is an extracellular deposit composed of β-amyloid protein, and the tangle, which is an
intracellular deposit of tau protein. An important gene that has been implicated in the
cause of AD codes for the amyloid precursor protein (APP).
Strong evidence suggests that the main constituent of the plaque,β-amyloid peptide
(Aβ), exerts a prominent role in the cause, initiation and progression of AD. Thus AD
appears to arise from the abnormal deposition of a protein. Aβis derived from prote-
olytic cleavage of amyloid precursor protein (APP), an integral membrane protein.
APP is cleaved by the sequential actions of three unique proteases, called α-,β-, and
γ-secretases. Each secretase cleaves at a unique site (see figure 8.7).
8.3.2 Targeting Proteins Endogenous to Other SpeciesIt is also possible to design drugs around proteins that are exogenous to humans but
endogenous to other species. As discussed in chapter 3, exogenous molecules may be
pursued as potential lead compounds in drug discovery. By designing drugs using pro-
teins that are endogenous to other species, it is sometimes possible to exploit targets in
humans that do not have messenger molecules. Although there are many examples of
such proteins, two illustrative examples are presented:
- Fish antifreeze proteins
- Snail conotoxins
Both of these “proteins from the sea” offer opportunities for drug design.
ENDOGENOUS MACROMOLECULES 515