Recent Advances in Prion Chemotherapeutics

Abstract

The transmissible spongiform encephalopathies are rapidly progressive and invariably fatal neurodegenerative diseases for which there are no proven efficacious treatments. Many approaches have been undertaken to find ways to prevent, halt, or reverse these prion diseases, with limited success to date. However, as both our understanding of pathogenesis and our ability to detect early disease increases, so do our potential therapeutic targets and our chances of finding effective drugs. There is increasing pressure to find effective decontaminants for blood supplies, as variant Creutzfeldt Jakob Disease (vCJD) has been shown to be transmissible by blood, and to find non-toxic preventative therapies, with ongoing cases of Bovine Spongiform Encephalopathy (BSE) and the spread of Chronic Wasting Disease (CWD). Within the realm of chemotherapeutic approaches, much research has focussed on blocking the conversion of the normal form of prion protein (PrPc) to its abnormal counterpart (PrPres). Structurally, these chemotherapeutic agents are often polyanionic or polycyclic and may directly bind PrPc or PrPres, or act by redistributing, sequestering, or down-regulating PrPc, thus preventing its conversion. There are also some polycationic compounds which proport to enhance the clearance of PrPres. Other targets include accessory molecules such as the laminin receptor precursor which influences conversion, or cell signalling molecules which may be required for pathogenesis. Of recent interest are the possible neuroprotective effects of some drugs. Importantly, there is evidence that combining compounds may provide synergistic responses. This review provides an update on current testing methods, therapeutic targets, and promising candidates for chemical-based therapy.

Prions

“…Many compounds that inhibit conversion have been identified, including polysulfated anions, dextrans, Congo red dye, oligonucleotides, and cyclic tetrapyrroles (for reviews, see Trevitt and Collinge [2006]; Sim and Caughey [2009]; Silber [2010]). Effective treatment for prion disease is hampered by the difficulty of these and other putative therapeutics to access the CNS, and by the difficulty of identifying small molecules that can prevent the protein -protein interactions that result in propagation of alternatively folded protein isoforms.…”

Insights from Therapeutic Studies for PrP Prion Disease

“…Researchers have made considerable effort to search for antiprion drugs or compounds using in silico screening, in vitro models, persistently prion-infected cell models, and prion-infected rodent models (Trevitt and Collinge 2006;Sim and Caughey 2009). In this section, we focus on drugs and compounds recently tested in CJD patients.…”

“…As already described, many compounds or biological materials have been discovered to have antiprion activity related to the inhibition of PrP Sc formation or the enhancement of PrP Sc degradation through a combination of in silico, in vitro, prion-infected cell models, and prioninfected animal screening (Sim and Caughey 2009;Teruya et al 2009). Among these models, prion-infected cell models have been the most frequently used since Congo red and polyanionic glycans were found to possess antiprion activity (Caughey and Race 1992;Caughey and Raymond 1993).…”

Efficacy and Mechanism of a Glycoside Compound Inhibiting Abnormal Prion Protein Formation in Prion-Infected Cells: Implications of Interferon and Phosphodiesterase 4D-Interacting Protein

“…Various antiprion compounds or biological materials reportedly inhibit PrPsc/res formation in vitro or in prioninfected cells (3)(4)(5). Some compounds and biological materials reportedly extend the incubation periods in prion-infected animals.…”