Polyproline Tri‐Helix Macrocycles as Nanosized Scaffolds to Control Ligand Patterns for Selective Protein Oligomer Interactions

Abstract

cells circulation are governed. [2] While many binding events take place within lipid microdomains on cell membranes, receptors can assemble into multireceptor complexes and exchange information directly through protein contact. [3] As the combination of these receptors can lead to alternative outcome in the signaling process, in addition to traditional studies based on monomeric receptor, multiple neighboring receptors would preferably be concurrently investigated at their native oligomeric state on the intact cell membrane for a better understanding. To this end, knowing how the receptors arrange on the plasma membrane is essential not only to reveal how their combination leads to functions but also to help synthetic chemists to create customized molecules to manipulate such processes. The asialoglycoprotein receptor (ASGPR), a galactose/ GalNAc-binding hepatic protein employed for drug delivery to hepatocytes, represents an example to address this issue as it forms oligomers by the combinations of two receptor subtypes. [4] Without detailed oligomeric structure, the distances between three ligand-binding sites of ASGPR trimer were estimated at 15, 20, and 25 Å by the glycan-binding studies. [5] A strategy to precisely control the patterns of multiple ligands [6] would aid in probing the ASGPR arrangement correlated to its function and manipulating the selectivity for the drug delivery. Toward this goal, a promising, yet challenging, approach is to develop an artificial molecular platform to control ligand patterns (Figure 1a).Ligand patterning is also an important factor for carbohydrate-lectin binding, which usually involves multiple simultaneous binding events to enhance the overall strength and allow for recognition. The concept of multivalent binding pioneered by Lee [7] and continued by others with thermodynamics explanations [8] has initiated the development of scaffolds supporting multiple glycan ligands to elicit strong interaction with proteins. [9] Glycoliposomes/micelles, [10] glycodendrimers, [11] glycopolymers, [12] and glycoclusters (including glycocyclopeptides) [9c,13] are among popular glycoconjugates that significantly enhanced binding avidity. However, protein-carbohydrate interaction is usually accompanied by cross-reactivity allowing a glycan ligand to interact with different Multivalent ligand-receptor interactions play essential roles in biological recognition and signaling. As the receptor arrangement on the cell surface can alter the outcome of cell signaling and also provide spatial specificity for ligand binding, controlling the presentation of ligands has become a promising strategy to manipulate or selectively target protein receptors. The lack of adjustable universal tools to control ligand positions at the size of a few nanometers has prompted the development of polyproline tri-helix macrocycles as scaffolds to present ligands in designated patterns. Model lectin Helix pomatia agglutinin has shown selectivity toward the matching GalNAc ligand pattern matching its binding sit...

Comprehensive characterization of polyproline tri-helix macrocyclic nanoscaffolds for predictive ligand positioning

“…38,45,46 In our previous investigation, we observed that the strain which arose from cyclization of the polyproline tri-helix peptide to the PP3M scaffold promoted the PPI conformation for some sizes of the scaffolds in 1-propanol. 17,34 Herein, as shown in Fig. 2b, we found that the CD spectra measured for scaffolds 1 and 2, as well as the linear tri-helix counterparts 17 and 18, in 1-propanol had the characteristics of the PPII helix (Fig.…”

“…9,10 The combination of its unique structure and biocompatibility has allowed researchers to control the directions and spacing of the ligands attached to the proline ring under aqueous conditions for a variety of biomedical-related applications. 11–17…”

“…9,10 The combination of its unique structure and biocompatibility has allowed researchers to control the directions and spacing of the ligands attached to the proline ring under aqueous conditions for a variety of biomedical-related applications. [11][12][13][14][15][16][17] Previously, our group took advantage of these features to create polyproline tri-helix macrocyclic (PP3M) scaffolds to control ligand patterns at the nanoscale. This design has several advantages over other popular cyclic scaffolds.…”

“…These breakthroughs have enabled investigations on how ligand patterns affect the avidities to protein oligomers and cell surface receptors. 17 …”

pH-Responsive Polypeptide-Based Smart Nano-Carriers for Theranostic Applications

“…Further, the l -proline-based nanogel reported as a successful pH-switcher [128]. The recent report based on pPro tri-helix macrocycles as nanosized scaffolds suggested that they were capable to probe the rearrangement of receptors on the cell surface and manipulated signalling or cell recognition as nanomedicine [129].…”