Generation of Dynamic Combinatorial Libraries Using Hydrazone‐Functionalized Surface Mimetics

Abstract

Dynamic combinatorial chemistry (DCC) represents an approach, whereby traditional supramolecular scaffolds used for protein surface recognition might be exploited to achieve selective high affinity target recognition. Synthesis, in situ screening and amplification under selection pressure allows the generation of ligands, which bear different moieties capable of making multivalent non‐covalent interactions with target proteins. Generic tetracarboxyphenyl porphyrin scaffolds bearing four hydrazide moieties have been used to form dynamic combinatorial libraries (DCLs) using aniline‐catalyzed reversible hydrazone exchange reactions, in 10 % DMSO, 5 mm NH4OAc, at pH 6.75. High resolution mass spectrometry (HRMS) was used to monitor library composition and establish conditions under which equilibria were established.

Dynamic Amino Acid Side‐Chains Grafting on Folded Peptide Backbone**

“…Changes in library composition upon introduction of the target are thus exploited to probe favorable interactions. DCC has been barely used in peptide and peptidomimetic chemistry but few example are reported: [7,8] to assemble peptides fragments into supramolecular 3D protein‐like structure, [9–11] to create peptide bonds between amino acids surrogates [12,13] or to graft side chains either on a flexible polymer backbone [14,15] or a rigid organic scaffold [16–18] . The covalent reversible functionalization of a well‐ordered peptide scaffold has been also reported [19] .…”

“…DCC has been barely used in peptide and peptidomimetic chemistry but few example are reported: [7,8] to assemble peptides fragments into supramolecular 3D protein-like structure, [9][10][11] to create peptide bonds between amino acids surrogates [12,13] or to graft side chains either on a flexible polymer backbone [14,15] or a rigid organic scaffold. [16][17][18] The covalent reversible functionalization of a well-ordered peptide scaffold has been also reported. [19] Combination of such a folded scaffold with dynamic combinatorial method has never been published to date.…”

Dynamic Amino Acid Side-Chains Grafting on Folded Peptide Backbone

“…DCC has been barely used in peptide and peptidomimetic chemistry but few example are reported: 7,8 to assemble peptides fragments into supramolecular 3D protein-like structure, [9][10][11] to create peptide bonds between amino acids surrogates 12,13 or to graft side chains either on a flexible polymer backbone 14,15 or a rigid organic scaffold. [16][17][18] The covalent reversible functionalization of a wellordered peptide scaffold has been also reported. 19 Combination of such a folded scaffold with dynamic combinatorial method has never been published to date.…”

Proteomimetic surface fragments distinguish targets by function

“…[1][2][3] Although pioneering studies demonstrated the possibility of ribosome-assisted coupling of amino acids with non-natural backbones, [4][5][6][7] in vitro directed evolutionary approaches 8 are not routinely available for searching and optimization of fundamentally xenobiotic surface mimetic structures. [9][10][11] Four major experimental chemical approaches and their combinations have been applied to address this problem: (i) screening of large surface mimetic libraries, 10,12,13 (ii) topdown mutational design based on known ligands, [14][15][16][17][18][19][20][21] (iii) bottom-up design and assembly starting from structural hypotheses, 3,[22][23][24][25][26][27][28][29][30][31] and (iv) the fragment-centric system chemistry approach leading to self-assembling ligands. 32 Recent theoretical and experimental results strongly support that fragment-centric design built on recognition elements of reduced structural complexity is highly promising for the construction of surface mimetic ligands.…”