Probing the proteolytic stability of beta-peptides containing alpha-fluoro- and alpha-hydroxy-beta-amino acids.
One of the benefits of beta-peptides as potential candidates for biological applications is their stability against common peptidases. Attempts have been made to rationalize this stability by altering the electron availability of a given amide carbonyl bond through the introduction of polar substituents at the alpha-position of a single beta-amino acid. Such beta-amino acids (beta-homoglycine, beta-homoalanine), containing one or two fluorine atoms or a hydroxy group in the alpha-position, were prepared in enantiopure form. A versatile method for preparing these alpha-fluoro-beta-amino acids by the homologation of appropriate alpha-amino acids and C-OH->C-F or C=O-->CF(2) substitution with DAST, is described. Consequently, a series of beta-peptides possessing an electronically modified residue at the N terminus or embedded within the chain was synthesized, and their proteolytic stability was investigated against a selection of enzymes. All ten beta-peptides tested were resilient to proteolysis. Introducing a polar, sterically undemanding group, into the alpha-position of beta-amino acids in a beta-peptide chain does not appear to facilitate localized or general enzymatic degradation.
Hook
David F
DF
Laboratorium für Organische Chemie, Eidgenössischen Technischen Hochschule, Wolfgang-Pauli-Strasse 10, 8093 Zürich, Switzerland.
Gessier
François
F
Noti
Christian
C
Kast
Peter
P
Seebach
Dieter
D
D000596:Amino Acids / Q000737:chemistry*; D004798:Enzymes / Q000737:chemistry / Q000378:metabolism; D005461:Fluorine / Q000737:chemistry*; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D015202:Protein Engineering / Q000379:methods*
D000596:Amino Acids; D004798:Enzymes; D010455:Peptides; D005461:Fluorine