Knocking off HSPs. How?

Emir Khatipov khatipovNO at NOuchicago.edu
Thu May 9 11:00:55 EST 2002


"D.K." <dk at no.email.thankstospam.net> wrote in message
news:abcv6s$q9u$1 at news.doit.wisc.edu...
> "Emir Khatipov" <khatipovNO at NOuchicago.edu> wrote:
> >I would appreciate if someone could help me to solve a rather tricky
riddle.
> >
> >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?
> >
> >The reason I am asking is the following. I am trying to develop compounds
> >(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, so I am trying to
> >examine if there is anything known about the ways to dissociation these
> >complexes in vivo. I tried to search literature on the subject, but did
not
> >dig out anything useful so far.
>
> Emir,
>
> The easiest way to dissociate these complexes is to add steroids :-)
>
> No, seriously: add your compound X with a not so potent steroid
> (one that has lower affinity for SR). Whether or not your concerns
> are justified, doing this should allow you to screen for a potent
> inhibitor of steroid translocation into nucleus.

It's not an inhibitor of translocation I am looking for, but a specific SR
binder that can be used for tissue-specific targeting of (e.g.) drugs (not
necessarily SR-related ones). Some SRs are good tissue-specific markers. If
I am not lucky enough, the first compounds I screen will have weaker
affinity to SRs than the weakest steroids, and I will have to apply
factorial structure-function analysis to design stronger binders. Another
problem is that the weaker binding steroids, as well as many other steroids,
are controlled substances and are not available on the market (at least as
far as I know).

Is there anything known about how HSP's binding to proteins is affected by
redox potential, drugs, interactions with other proteins, temperature, etc.?
Chemicals ot physical factors might be easier to explore. However,
biological approach might work as well. For example, there could be a
protein P that can interact with HSP and cause dissociaton of the latter
from the SR. By controlling levels of P it would be possible to affect
binding of SR to HSP and thus allow compound X to bind SR. I have quite a
limited knowledge on HSPs, and assume that the reason I did not find any
relevant information so far in a vast amount of literature on HSP is because
the papers I am looking for are among those "shy" ones that never get
referenced in databases....

Any more ideas?
Emir

>
> Anything wrong with such approach? Of course you'll get lots
> of inhibitor that block other steps, but this _always_ happen
> whenever you attempt to do anything in vivo.
>
> DK





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