Design and Combinatorial Development of Shield-1 Peptide Mimetics Binding to Destabilized FKBP12

Abstract

On the basis of computational design, a focused one-bead one-compound library has been prepared on microparticleencoded PEGA 1900 beads consisting of small tripeptides with a triazole-capped N-terminal. The library was screened towards a double point-mutated version of the human FKBP12 protein, known as the destabilizing domain (DD). Inspired by the decoded library hits, unnatural peptide structures were screened in a novel on-bead assay, which was useful for a rapid structure evaluation prior to off-bead resynthesis. Subsequently, a series of 19 compounds were prepared and tested using a competitive fluorescence polarization assay, which led to the discovery of peptide ligands with low micromolar binding affinity towards the DD. The methodology represents a rapid approach for identification of a novel structure scaffold, where the screening and initial structure refinement was accomplished using small quantities of library building blocks.

Aza-Residue Modulation of Cyclic d,l-α-Peptide Nanotube Assembly with Enhanced Anti-Amyloidogenic Activity

“…Azapeptides 2 – 5 , 7 , and 8 were purified by reverse-phase HPLC (Table S1). The reaction of [azaPra 5 ]- 1 ( 8 ) with TMS–N 3 in the presence of CuSO 4 ·5H 2 O and sodium ascorbate in MeOH/water gave aza-triazole-3-alanine cyclopeptide 6 in 78% yield after HPLC purification and validated the potential to conjugate azides onto the azaPra handle. , …”

“…Azapeptides 2 – 7 were synthesized by a modified solid-phase peptide synthesis method. , Aza-residues were introduced into the linear sequence as N -Fmoc-aza-amino acid chlorides 11a–f prior to peptide elongation, resin cleavage, cyclization, and removal of side-chain protection in solution (Scheme ). In addition, aza-propargylglycine [azaPra 5 ]- 1 ( 8 ) was synthesized by the same strategy and used to prepare the azaTal residue by a copper-catalyzed azide alkyne cycloaddition (CuAAC) reaction , and alkylation with propargyl bromide …”

Bottom-Up Design Approach for OBOC Peptide Libraries

“…This paper, written for the special issue Peptides and Peptide Technologies: A Themed Issue in Honor of Professor Morten Meldal on the Occasion of His Citation Laureates, wants to pay tribute to his pioneering work on one-bead-one-compound (OBOC) peptide libraries [ 1 , 2 , 3 , 4 , 5 , 6 ] and development of advanced synthetic methodologies on solid supports [ 7 , 8 , 9 , 10 , 11 ].…”

“…Several examples have been developed and characterized following this scheme [ 12 , 16 , 20 , 21 , 22 ]. In addition, a variety of optimized methods have been proposed to improve both synthesis and screening processes, such as the use of color coding [ 23 ], fluorescent dyes [ 17 ], immobilization of beads on solid supports [ 24 ] and others [ 3 , 14 , 18 , 21 , 25 ]. This typical top-down design approach to OBOC peptide libraries leads to the efficient synthesis of large libraries but often fails in the step of sequence identification after screening.…”

“…This typical top-down design approach to OBOC peptide libraries leads to the efficient synthesis of large libraries but often fails in the step of sequence identification after screening. The unambiguous confirmation of peptide sequences remains a major bottleneck due to mixture complexity [ 3 , 12 , 26 ]. Such complexity often hampers straightforward sequence elucidation due to the co-existence of palindromic or isobaric peptides, partial sequence overlapping and physico-chemical similarity of peptide permutations [ 27 ].…”