An Immunomodulatory Peptide Dendrimer Inspired from Glatiramer Acetate

• Published in: Angewandte Chemie International Edition Vol. 60; no. 50; pp. 26403 - 26408
• Main Authors: Erzina, Dina, Capecchi, Alice, Javor, Sacha, Reymond, Jean‐Louis
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 06-12-2021; John Wiley and Sons Inc
• Edition: International ed. in English
• Subjects: Amino acid composition; Amino acids; Autoimmune diseases; Cell Differentiation - drug effects; Communication; Communications; Copolymer 1; Cytokines; Dendrimers; Dendrimers - chemical synthesis; Dendrimers - chemistry; Dendrimers - pharmacology; Glatiramer Acetate; Glatiramer Acetate - chemistry; Glatiramer Acetate - pharmacology; Humans; Immune system; Immunomodulation; Immunosuppressive Agents - chemical synthesis; Immunosuppressive Agents - chemistry; Immunosuppressive Agents - pharmacology; Inflammation; Interleukins; Monocytes; Monocytes - drug effects; Multiple sclerosis; Peptides; Peptides - chemical synthesis; Peptides - chemistry; Peptides - pharmacology; Polypeptides; Receptors, Interleukin-1 - antagonists & inhibitors; Glatiramer Acetate; immunomodulation; peptides; dendrimers; multiple sclerosis
• ISSN: 1433-7851; 1521-3773; 1521-3773
• DOI: 10.1002/anie.202113562

Glatiramer acetate (GA) is a random polypeptide drug used to treat multiple sclerosis (MS), a chronic autoimmune disease. With the aim of identifying a precisely defined alternative to GA, we synthesized a library of peptide dendrimers with an amino acid composition similar to GA. We then challenged the dendrimers to trigger the release of the anti‐inflammatory cytokine interleukin‐1 receptor antagonist (IL‐1Ra) from human monocytes, which is one of the effects of GA on immune cells. Several of the largest dendrimers tested were as active as GA. Detailed profiling of the best hit showed that this dendrimer induces the differentiation of monocytes towards an M2 (anti‐inflammatory) state as GA does, however with a distinct immune marker profile. Our peptide dendrimer might serve as starting point to develop a well‐defined immunomodulatory analog of GA.
To identify an alternative to the polymeric peptide drug Glatiramer Acetate (GA) used to treat multiple sclerosis, we tested peptide dendrimers with a size and composition similar to that of GA for their ability to induce the release of the cytokine IL1‐Ra from primary human monocytes. The best dendrimer is as active as GA and is shown by fluorescence labelling to internalize into monocytes and to trigger a distinct anti‐inflammatory response.