"Emir Khatipov" <khatipovNO at NOuchicago.edu> wrote:
>>"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.
I did not think you are after inhibitor of translocation. Rather, I suggested
to use translocation as a measure in screen. If your staff X specifically
binds to inactive form of SR, it is almost certain it will inhibit activation
by steroids.
In any case, that geldanamycin substance pointed out elsewhere in
this thread sounds like it might be just what you are looking for.
>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).
Not a problem. You can buy any kind of scary drug for research
purposes if you can prove you really need it.
Apart from all that, if the whole idea is tissue-specific targeting of drugs,
IMHO, SR binder is not a promising approach. To bind SR, the stuff would
have to get into the cell to begin with. If so, I can't see how it can be
called targeting, for the stuff would have to be membrane permeable
(and specific binding to specific SR would not cause real accumulation
of the drug).
Standard extracellular receptors and conjugates with their ligands
seem to fit the bill better (but I guess it's been tried extensively and
never worked adequately).
DK
