Workshop-Synthetic Peptides for Biological Studies: Minimizing Peptide
Degradation.
Chaired by Gregg Fields.
Presentations by - Gregg Fields (University of Minnesota at Minneapolis) and
-
Steven A. Kates (Biosearch Division of PerSeptive Biosystems).
The development of "peptide drugs" has often been hindered by the
relatively short half-life of peptides in vivo. In particular, peptides are
hydrolyzed readily by enzymes such as amino- and carboxy-peptidases.
Peptide degradation may be minimized by one of two simple, general
approaches: conformational constraint of the peptide sequence and
incorporation of D-amino acid analogs. Conformational constraints limit the
peptide from assuming a vast array of flexible states, which potentially
reduce the probability of the peptide "fitting" enzyme binding pockets.
Constraints may be introduced by disulfide bridging or by lactamization
using amino acid sidechains or free peptide amino and/or carboxy termini.
Orthogonal approaches, compatible with the mild conditions of Fmoc
chemistry, have made the introduction of these constraints possible with
resin-bound peptides. The solid-phase mode may be advantageous due to a
pseudo-dilution phenomenon, a kinetic effect that favors intramolecular
reactions over intermolecular reactions (cyclodimerizations and
cyclo-oligomerizations). Methods for on-resin (heterodetic) disulfide bond
and (homodetic) lactam formation will be described. This discussion will
focus on the requirements for an extra level of selectively cleavable
protecting groups and anchoring linkages. The introduction of D-amino acid
analogs to inhibit enzymatic degradation is straightforward but creates a
potential problem of altering the desired recognition of the peptide. Two
strategies for using D-amino acids, assembling D-enantiomer "mirror image"
peptides and reverse-sequence all-D "retro-inverso" peptides, will be
discussed. In particular, examples of both the success and failure of using
D-amino acid peptides will be given, as well as potential guidelines for
when each strategy may be applicable.
Return to the The ABRF Home Page
Created: 27th July 1995
Last modified: 27th July 1995