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<DIV dir=ltr align=left><SPAN class=415452718-27012011><FONT color=#0000ff
size=2 face=Arial>Hello Mike. The thermal unfolding of erythropoietin starts (5%
point) at 36 C under near-physiological conditions. That is, it is already
starting to unfold at <EM>in vivo</EM> temperatures! The actual Tm is near
47 C. What saves this situation is that the high glycosylation helps to make the
unfolding completely reversible (at least under <EM>in vitro</EM> conditions). I
doubt you will find any other therapeutics with Tm lower than that. For details
see [<FONT size=2>Arakawa, T., Philo, J. S., and Kita, Y. (2001). Kinetic and
thermodynamic analysis of thermal unfolding of recombinant erythropoietin.
<I>Biosci. Biotechnol. Biochem. </I>65, 1321-1327</FONT>]. You can also see some
of these unfolding curves (by CD) on our APL web site, <A
href="http://www.ap-lab.com/circular_dichroism.htm#thermal_cd">http://www.ap-lab.com/circular_dichroism.htm#thermal_cd</A></FONT></SPAN></DIV>
<DIV dir=ltr align=left><SPAN class=415452718-27012011><FONT color=#0000ff
size=2 face=Arial></FONT></SPAN> </DIV>
<DIV dir=ltr align=left><SPAN class=415452718-27012011><FONT color=#0000ff
size=2 face=Arial>John</FONT></SPAN></DIV><BR>
<DIV dir=ltr lang=en-us class=OutlookMessageHeader align=left>
<HR tabIndex=-1>
<FONT size=2 face=Tahoma><B>From:</B> rasmb-bounces@rasmb.bbri.org
[mailto:rasmb-bounces@rasmb.bbri.org] <B>On Behalf Of </B>Doyle,
Michael<BR><B>Sent:</B> Thursday, January 27, 2011 10:00 AM<BR><B>To:</B>
rasmb@rasmb.bbri.org<BR><B>Subject:</B> [RASMB] Protein Therapeutic Lower
Stability Limit<BR></FONT><BR></DIV>
<DIV></DIV>
<DIV class=Section1>
<P class=MsoNormal>All:<o:p></o:p></P>
<P class=MsoNormal><o:p> </o:p></P>
<P class=MsoNormal>Does anyone know if there is public information (literature)
about protein therapeutic drugs in the clinic or market that have unusually low
thermal denaturation Tm values? Tm values are of course very dependent on
solution conditions, and it is not clear to me how Tm values measured in vitro
compare to the Tm the protein would have in the crowded in vivo setting.
Regardless, for benchmark purposes, what are the lowest Tm values of
clinical/marketed protein therapeutics as measured by DSC or other in vitro
thermal methods under say, neutral pH and physiologic-like salt
conditions?<o:p></o:p></P>
<P class=MsoNormal><o:p> </o:p></P>
<P class=MsoNormal>Mike<o:p></o:p></P></DIV><BR>
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