Knocking off HSPs. How?

Emir Khatipov khatipovNO at NOuchicago.edu
Thu May 30 17:08:06 EST 2002


"Artem Evdokimov" <AEVDOKIMOZ at cinci.rr.com> wrote in message
news:_dFC8.67694$Ez5.16529678 at typhoon.neo.rr.com...
> > When not bound to steroids, steroid receptors (SRs) form complexes with
> heat
> > shock proteins (HSPs) in the cytoplasm. Upon activation with steroids,
the
> > receptors change conformation, lose the coat of HSPs and penetrate the
> > nucleus to activate transcription of target genes.
> > Does anybody know or could come up with an idea how to dissociate SRs
from
> > HSPs by some physical or chemical stimulation?
>
> Apart from the ideas suggested here by others - you could consider
> denaturation & renaturation. Pain in the neck, though. High concentrations
> of betains and related compounds may work without completely denaturing
the
> target. Expression outside the cell (in suitable system) may work too. I
am
> still not sure if you seek to obtain competent pure receptor or you need
to
> 'denude' the receptor while it's in the cell. :)

I am targeting the intracellular SR.

>
> > (small molecules, including peptides) that would bind SRs in inactive
> form.
> > I am a priori concerned that due to sterical hindrances those compounds
> will
> > not be able to bind inactive SRs associated with HSPs
>
> Out of curiosity - if your target protein is always coated by HSP's in the
> cytoplasm, then why do you think that the naked protein is a good target
for
> your proto-therapeutic ? After all, in the cell it will most likely live
in
> complex with HSP's or with the steroids most of the time. Would it be
easier
> to target the steroid-bound receptor, on its way to the nucleus or even
the
> HSP-protein complex ?
That should not be a problem in the clinic to administer the same geldamycin
along with the new agent. Moreover, it would be nice to have a
two-functional agent that would bind to SR and affect (in any way) its
activity.

>
> Good luck,
>
> A.G.E.
>
>





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