Application of Combinatorial Procedures in the Search for Serine-Protease-Like Activity with Focus on the Acyl Transfer Step

Abstract

Recursive deconvolution of a 729-membered peptide library has identified three active sequences, in which both Ser and His are present in one of the two tripeptidic chains generated on a steroidal scaffold (see structural formula), for the cleavage of an activated p-nitrophenyl ester. This combinatorial approach aims at searching for serine-protease-like activity.

Bile Acids as Building Blocks of Supramolecular Hosts

“…have synthesized two methyl cholate derivatives ( 31a-b , Figure 20 ) with three independently-addressable, rigidly-positioned functional groups [ 133 ]. The free acid of 31b has been used in constructing the hexapeptide library containing 729 compounds [ 134 ]. The previously mentioned “triaza-analogue” of methyl cholate [ 106 , 108 ] seems also to be a versatile starting material for combinatorial libraries.…”

Identification and optimization of short helical peptides with novel reactive functionality as catalysts for acyl transfer by reactive tagging

“…The de Clercq group, in particular, has followed a similar course for the identification of peptides that accelerate serine O-acylation, though a mention of reversible histidine N-acylation is made. [7][8][9] The focus of our efforts was on peptide secondary structures that maximized our ability to convert peptide hit sequences into active site structures that reliably position critical side-chains into 3-dimensional space. Short peptides that take on helical structure in organic solvent (α-helix and/or 3 10 -helix) were selected as the scaffold because the variable i + 3/i − 3 and i + 4/i − 4 positions in the linear sequence place functionality in close proximity to the i-position, to which a histidine (His) residue was placed (Fig.…”

Synthesis of Functionalised Nucleosides for Incorporation into Nucleic Acid-Based Serine Protease Mimics

“…In a first approach, we developed non-peptidic organic molecules containing an array of functional groups in a suitable geometry for possible hydrolytic activity [22]. In a second combinatorial approach, a dipodal scaffold based on a cholic acid template was synthesized and two independent peptide chains were attached, each containing one residue of the catalytic triad [23,24]. In addition, a model based on a tripodal scaffold, with a rigid structure possessing three independent functionalised peptide chains, was also synthesized [25].…”