Clue for Possible Treatment of Prion Diseases

While
looking for information for my last post, I encountered another
interesting article at PNAS.  This one is about a new molecule
that improved survival in mice infected with href="http://www.aphis.usda.gov/lpa/pubs/fsheet_faq_notice/fs_ahscrapie.html"
rel="tag">scrapie.  



Scrapie is one of the href="http://en.wikipedia.org/wiki/Transmissible_spongiform_encephalopathy">transmissible
spongiform encephalopathies (TSE).
 Transmissible, because the infection can be transmitted from
one creature to another; spongiform, because the brain tissue of an
infected animal looks like a sponge, when viewed with a microscope;
encephalopathy, because it causes disease of the brain.



There is a family of TSEs.  All are caused by href="http://www.cdc.gov/ncidod/dvrd/prions/index.htm">prions;
all are invariably fatal.  Although they may have a long
incubation time, they progress rapidly to death once symptoms become
apparent.  Thus, any clue about a possible treatment is
encouraging to see...



There are many prion diseases; some primarily affect humans, while
others affect animals.  But humans who eat infected animals
can get infected themselves.  That is why mad cow disease
(Bovine Spongiform Encephalopathy) is so worrisome.

Human
Prion Diseases

• Creutzfeldt-Jakob
  Disease (CJD)
• Variant
  Creutzfeldt-Jakob Disease
  (vCJD)
• Gerstmann-Straussler-Scheinker
  Syndrome
• Fatal
  Familial Insomnia
• Kuru

Animal Prion Diseases

• Bovine
  Spongiform Encephalopathy (BSE)
• Chronic
  Wasting Disease (CWD)
• Scrapie
• Transmissible
  mink encephalopathy
• Feline
  spongiform encephalopathy
• Ungulate
  spongiform encephalopathy

The PNAS article, href="http://www.pnas.org/cgi/content/abstract/0702671104v1">Hot
spots in prion protein for pathogenic conversion, is not
open-access.



However,
a nice summary is openly available.  The link appears to not
be a permalink, so I am going to just copy the whole thing here.
 You still need subscription or institutional access to read
the actual article.



Incidentally, I find myself linking to closed-access articles less and
less, but this one had a cool picture...

href="http://www.pnas.org/misc/highlights.shtml#Blocking">Blocking
prion formation

    The conversion of a prion protein from
its native form to its pathogenic form is poorly understood and
difficult to stop. Kazuo Kuwata et al. identified a
molecule that can interrupt the conversion of the scrapie protein to
its infective conformation. The authors used a computer screening
program to identify candidate molecules that could stabilize the native
form by filling a pocket in the protein that deforms as it moves from
its native state to a temporary higher energy form. From a list of
320,000 potential compounds, their program reduced the list to 624.
Further refinement reduced the list to 59, 44 of which were tested in
mouse neuronal cell cultures. One, called GN8, safely blocked the
transformation of the scrapie protein in a dose-dependent manner. Live
mice infected with the scrapie protein survived longer when given GN8.
The authors also found that GN8 rescues the prion protein from its
pathogenic deformation by intercalating its hot spots. A molecule like
GN8 could be used to treat prion diseases, and computer-based screens
may identify more suitable compounds. The authors say that their
proposed strategy, termed "dynamics based drug design," may be
applicable to other protein misfolding diseases. — P.D.

There are many obstacles to overcome before anything potentially
therapeutic for humans is developed.