constrained random peptide libraries

Dom Spinella dspinella at chugaibio.com
Tue Aug 12 13:27:47 EST 1997


Scott Vande Pol writes:
> We plan to do some fishing into a random peptide library and would like to
> know the experience of those that have used constrained peptides vs
> unconstrained peptides. Are peptides that are removed from their
> constrained vectors likely to still function in an unconstrained context? 
> ie is the greater likelyhood of getting a "hit" on the constrained library
> offset by the potential lack of function when the peptides are subsequently
> used unconstrained?
> 
> -- 
> Scott Vande Pol
> Case Western Reserve University
> Department of Pathology
> Cleveland Oh. 44106
> sbv at pop.cwru.edu

Its not clear what kind of peptide library you are referring to.  Are
you working with phage display or some other system? Also, what do you
mean by "constrained"?  Do you mean that there is a disulfide linkage at
defined positions in the peptide giving a defined ring size?  Or do you
mean that your peptide is inserted into a molecular scaffold such as IgG
or other molecule (e.g. Tandamestat) that has been used for this
purpose.  In general, constrained peptides have a better chance of
providing hits as there are fewer conformations that can be assumed and
thus the entropic costs of binding are lower.  This has been established
in the phage display system with disulfide linkages.  In this case
however, the disulfide "constraint" is an integral part of the binding
moiety, and can be built into the synthetic peptide; eliminating the
linkage generally abrogates or at least reduces binding activity.  In
the case of more complex scaffolds, it is often the case that the
"unconstrained" peptide loses biologic activity altogether when isolated
from the parent scaffold.  Hope that helps.  -- D.G. Spinella



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