Drug Design Targeting Prions

Prion diseases have attracted immense attention over the past decade, prompted, in part, by the outbreak of mad cow disease in the United Kingdom. The most common prion disease is sporadic Creutzfeldt-Jakob disease (CJD). Clinically, CJD is characterized by a rapidly progressive dementia accompanied variably by early-onset seizures, insomnia, disordered movements, and psychiatric disturbances the disease is uniformly fatal. Histochemically, the principal pathological feature of prion disease is the abnormal accumulation of an amyloid-like material composed of prion protein (PrP), which is encoded by a single gene on the short arm of chromosome 20. 

The abnormal deposits found in the brains of CJD victims consist of an abnormal isoform of PrP. Prion protein is normally found in cells. Detailed structural studies show that normal cellular PrP (PrP ) is a soluble protein whose conformation is rich in a-helices with very little [3-sheet. The PrP protein extracted from the brains of CJD victims (i.e., PrP ) is identical in primary amino acid sequence to the normal PrP (PrP ). However, PrP has a much greater content of [3-sheet conformation with little a-helical structure. Thus PrP is neurotoxic because of its three-dimensional structure. When the 

Like any other protein, the molecular stmcture of the prion is subject to conformational flexibility and to various thermal-induced fluctuations between varying conformational states. However, if these fluctuations permit the PrP conformation to be attained, then this abnormal conformer promotes the widespread conversion of PrP to PrP , 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 a-helical PrP to P-sheet PrP may in principle be initiated by a seed PrP molecule 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 compounds with therapeutic potential polysulphated molecules and tricyclic molecules (e.g., phenothiazines, aminoacridines). These compounds bind to PrP and endeavor to inhibit the PrP to PrP cascade of conformational change. 

A high proportion of human and animal diseases are caused by viruses, from the common cold to poliomyelitis, rabies, hepatihs, and many others. Table 9.1 provides an overview of viruses causing diseases in humans. In the last two decades of the twentieth century, the emergence of the AIDS epidemic focused attention on the need to develop 

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