[RASMB] Protein Therapeutic Lower Stability Limit

[John Philo]

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 in vivo 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 in vitro conditions). I doubt you will
find any other therapeutics with Tm lower than that. For details see
[Arakawa, T., Philo, J. S., and Kita, Y. (2001). Kinetic and thermodynamic
analysis of thermal unfolding of recombinant erythropoietin. Biosci.
Biotechnol. Biochem. 65, 1321-1327]. You can also see some of these
unfolding curves (by CD) on our APL web site,
http://www.ap-lab.com/circular_dichroism.htm#thermal_cd
 
John

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From: rasmb-bounces at rasmb.bbri.org [mailto:rasmb-bounces at rasmb.bbri.org] On
Behalf Of Doyle, Michael
Sent: Thursday, January 27, 2011 10:00 AM
To: rasmb at rasmb.bbri.org
Subject: [RASMB] Protein Therapeutic Lower Stability Limit



All:

 

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?

 

Mike


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