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Peptide-polymer systems hold strong potential for applications in nanotherapeutics. Desmopressin, a synthetic analogue of the antidiuretic hormone arginine vasopressin, may serve as a valuable case of study in this context since it is a first-line treatment for disorders affecting water homeostasis, including diabetes insipidus. It also has an established use as a hemostatic agent in von Willebrand disease, and recently, its repurposing has been suggested as a neoadjuvant in the treatment of certain types of cancer. Despite its well-documented clinical uses, studies on the supramolecular organization of desmopressin and its association with polymers remain scarce, limiting the therapeutic benefits of these nanostructured arrays. Here, we investigate the self-assembly of desmopressin and its association with sodium polystyrene sulphonate (NaPSS), a potassium-binding polymer used to treat hyperkalemia. Using structural techniques such as small-angle X-ray scattering (SAXS), cryogenic transmission electron microscopy (cryo-TEM), and atomic force microscopy combined with infrared nanospectroscopy (AFM-IR), we identified that desmopressin associates with NaPSS to form hybrid fibrillar nanoassemblies characterized by β-turn enriched domains and the appearance of β-sheet content. In vitro cytotoxicity assays conducted on breast cancer cell lines MCF-7 and MDA-MB-231 showed that NaPSS/desmopressin complexes are well-tolerated by the non-metastatic MCF-7 cells while displaying inhibitory effects against the metastatic MDA-MB-231 cells. The findings presented here, which demonstrate the successful association between two clinically validated drugs and the ability of the hybrid matrix to modulate cell interactions, potentially contribute to the design of peptide-polymer therapeutic systems.

We investigate the physicochemical effects of pyroglutamination on the QHALTSV-NH 2 peptide, a segment of cytosolic helix 8 of the human C-X-C chemokine G-protein-coupled receptor type 4 (CXCR4). This modification, resulting from the spontaneous conversion of glutamine to pyroglutamic acid, has significant impacts on the physicochemical features of peptides. Using a static approach, we compared the transformation in different conditions and experimentally found that the rate of product formation increases with temperature, underscoring the need for caution during laboratory experiments to prevent glutamine cyclization. Circular dichroism experiments revealed that the QHALTSV-NH 2 segment plays a minor role in the structuration of H8 CXCR4; however, its pyroglutaminated analogue interacts differently with its chemical environment, showing increased susceptibility to solvent variations compared to the native form. The pyroglutaminated analogue exhibits altered behavior when interacting with lipid models, suggesting a significant impact on its interaction with cell membranes. A unique combination of atomic force microscopy and infrared nanospectroscopy revealed that pyroglutamination affects supramolecular self-assembly, leading to highly packed molecular arrangements and a crystalline structure. Moreover, the presence of pyroglumatic acid has been found to favor the formation of amyloidogenic aggregates. Our findings emphasize the importance of considering pyroglutamination in peptide synthesis and proteomics and its potential significance in amyloidosis.