RGD Cyclopeptide Equipped with a Lysine‐Engaging Salicylaldehyde Showing Enhanced Integrin Affinity and Cell Detachment Potency

Abstract

Salicylaldehyde (SA) derivatives are emerging as useful fragments to obtain reversible-covalent inhibitors interacting with the lysine residues of the target protein. Here the SA installation at the C terminus of an integrin-binding cyclopeptide, leading to enhanced ligand affinity for the receptor as well as stronger biological activity in cultured glioblastoma cells is reported.

Synthesis of Noncoded Amino Acids Bearing a Salicylaldehyde Tag for the Design of Reversible‐Covalent Peptides

“…As in our earlier work, [15,16] we selected dihydroxybenzaldehyde derivatives (i. e., 2,5-and 2,4-dihydroxybenzaldehydes: Figure 1D, compounds 1 a and 1 b, respectively), with the aim to exploit a second phenolic OH group in the aromatic ring (5-OH or 4-OH) as anchoring unit for the SA installation in the AA side chain. In particular, as illustrated by the retrosynthetic pathway in Scheme 1A, we planned the SA tag connection to the AA scaffold through a Williamson ether synthesis, using the phenolic OH as nucleophile and a leaving group on the AA side chain.…”

A Tight Contact: The Expanding Application of Salicylaldehydes in Lysine‐Targeting Covalent Drugs

“…[41] Our group has recently explored the tailored SA installation into peptide ligands, particularly at the N or C termini of a model cyclic peptide, bearing the ArgÀ GlyÀ Asp (RGD) as wellknown recognition sequence for integrin α V β 3 . [42] The latter features four solvent-exposed Lys near the peptide binding site, which lies at the interface of the protein subunits. Competitive binding assays indicated that the naive ligand strongly inhibits the binding of vitronectin (i. e., a natural integrin ligand bearing the RGD motif) to the receptor (IC 50 � 6 nM).…”

“…Considering the high frequency of Lys in proteins and the preferential expression of this amino acid on external protein layers, it can be foreseen that SAbearing compounds will be extensively applied in the future to hit undruggable targets and key protein-protein interactions. [42] The covalent docking figures were originally edited with Schrödinger Maestro graphical interface (Schrödinger Release 2021-1).…”

“…Our group has recently explored the tailored SA installation into peptide ligands, particularly at the N or C termini of a model cyclic peptide, bearing the Arg−Gly−Asp (RGD) as well‐known recognition sequence for integrin α V β 3 [42] . The latter features four solvent‐exposed Lys near the peptide binding site, which lies at the interface of the protein subunits.…”

“…B) Representative covalent docking pose of the SA‐bearing peptide 11‐SA where the cyclic peptide connected through the SA tag to the accessible Lys125 at the β 3 integrin subunit overlaps with the X‐ray structure of benchmark Cilengitide ligand (green). C) Representative covalent docking pose of the SA‐bearing peptide 12‐SA , where the forced interaction of the N‐terminal SA with the accessible β 3 Lys253 leads to a poor overlay of the cyclic peptide with Cilengitide (green) [42] . The covalent docking figures were originally edited with Schrödinger Maestro graphical interface (Schrödinger Release 2021–1).…”