CC chemokine receptors 2 (CCR2) and 5 (CCR5) are involved
in many
inflammatory diseases; however, most CCR2 and CCR5 clinical candidates
have been unsuccessful. (Pre)clinical evidence suggests that dual
CCR2/CCR5 inhibition might be more effective in the treatment of such
multifactorial diseases. In this regard, the highly conserved intracellular
binding site in chemokine receptors provides a new avenue for the
design of multitarget ligands. In this study, we synthesized and evaluated
the biological activity of a series of triazolopyrimidinone
derivatives in CCR2 and CCR5. Radioligand binding assays first showed
that they bind to the intracellular site of CCR2, and in combination
with functional assays on CCR5, we explored structure–affinity/activity
relationships in both receptors. Although most compounds were CCR2-selective, 39 and 43 inhibited β-arrestin recruitment
in CCR5 with high potency. Moreover, these compounds displayed an
insurmountable mechanism of inhibition in both receptors, which holds
promise for improved efficacy in inflammatory diseases.
Introduction of unnatural amino acids can significantly improve the binding affinity and stability of peptides. Commercial availability of such amino acids is limited, and their synthesis is a long and tedious process. We here describe a method that allows the functionalization of peptides directly on solid-support by converting lysine residues to Katritzky salts, and subjecting them to a photochemical Giese reaction under mild reaction conditions. The method avoids the need for amino acid synthesis and instead offers a late-stage modification route for rapid peptide diversification. While numerous modification approaches at the lysine amine have been described, this work provides the first example of deaminative functionalization of peptides at lysine. The two-step protocol is compatible with various substrates, lysine analogues, resins, and all proteinogenic amino acids. Finally, by leveraging solid-phase modification, this protocol facilitates the functionalization of longer peptides as was demonstrated using biologically relevant peptides of up to 15 amino acids.
Here we describe the application of photochemical decarboxylative arylation as a late-stage modification reaction for peptides. The reaction uses redox active esters of aspartic acid and glutamic acid on solid phase to provide analogues of aromatic amino acids. By using aryl bromides as arylation reagents a wide variety of amino acids can be accessed without having to synthesize them individually in solution. The reaction is compatible with proteinogenic amino acids and was used to perform a structure-activity relationship study on a PRMT5 binding peptide.
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