Prion protein as a target for therapeutic interventions
P. P. Liberski
Department of Molecular Pathology and Neuropathology,
Medical University of Lodz, Czechoslowacka st. 8/10; PL 92-216 Lodz,
Poland
Abstract: Transmissible spongiform encephalopathies (TSEs),
currently known as prion diseases, are neurodegenerative disorders of
the central nervous system (CNS) caused by an elusive infectious agent
called prion (proteinaceous infectious particle). These
dis-
orders include: kuru, Creutzfeldt Jakob disease (CJD) and its
variant (vCJD), GerstmannSträusslerScheinker (GSS)
disease and fatal familial insomnia (FFI) in humans, scrapie in sheep
and goats, bovine spongiform encephalopathy (BSE) or mad cow disease,
and chronic wasting disease (CWD) in cervids. According to the widely
accepted prion hypothesis, prion is an aggregate of the
abnormal isoform of prion protein (PrPSc). Prion protein
is a cell-derived glycoprotein (this normal isoform is called PrPc)
encoded by a gene on chromosome 20 in humans (PRNP). In familial forms
of TSEs, mutations within the ORF of PRNP are linked to the phenotypic
expression of the disease. TSEs are important from pub-
lic health perspective, and mad cow disease has created the greatest
threat to the safety of human food supply in modern times. vCJD threatens
the safety of the blood supply worldwide. Thus, to search for
effective therapy is more than an urgent task. In TSEs, aggregates
of PrPSc accumulate in the brain in a form of plaques, or
synaptic deposits. The conversion of PrPc into PrPSc
and subsequent deposits of PrPSc are targets for therapeutic
interventions. These include: tricyclic compoundsacridine and
phenothiazine derivatives; quinacrine; anti-PrPSc antibodies;
dendrimers; polyethylene antibiotics (amphotericin B, MS-8209); pentosan
polysulfate; and dextran sulfate. All these compounds are active in
many in vitro and
in vivo assays, but not proved definitely active in humans. Thus, albeit
interesting and promising, the chemotherapy of TSEs is still in the
infant phase.
*Lecture presented at the Polish-Austrian-German-Hungarian-Italian Joint Meeting on Medicinal Chemistry, Krak�w, Poland, 15-18 October 2003. Other presentations are published in this issue, pp. 907 -1032.
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