Proteins as Drugs and Drug Design Targets Non-Enzymes

3 PROTEINS AS DRUGS AND DRUG DESIGN TARGETS NON-ENZYMES 

A number of neurodegenerative disorders are characterized by neuronal damage that is induced by neurotoxic, aggregation-prone proteins. Various neurodegenerative diseases, including Alzheimer s disease ( caused by [l-amyloid deposits), prion disease 

1 Protein Folding Diseases Prion-Induced Dementia 

Prion diseases have attracted immense attention over the past decade. This attention was prompted, in part, by the outbreak of mad cow disease in the United Kingdom, an outbreak that ultimately involved humans. More recently, the identification of cows with mad cow disease in North America has emphasized the widespread nature of this problem. 

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 P-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 P-sheet conformation with little a-helical structure. Thus PrP is neurotoxic because of its three-dimensional structure. When the prion protein is predominantly in an a-helical conformation it is nontoxic when the prion protein is predominantly in a P-sheet conformation, it kills neurons. The prion protein is thus made neurotoxic not by its amino acid composition but by its conformation. This concept is both fascinating and terrifying. Prion diseases are transmissible thus prions are infectious agents. However, prions are not like bacteria or viruses, or other infectious microbes—they are simply protein molecules. Prions are not microbes with cell membranes and nucleic acids they are not living things. Indeed, prions are not even infectious molecules, they are infectious molecular shapes. 

---