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Scientific result | Health ＆ life sciences | Pharmacology
A team from SIMoS (DMTS) in collaboration with Sanofi shows that the introduction of non-natural sequences into an immunogenic peptide attenuates the immune response against this peptide, an approach that could guide the design of less immunogenic, and therefore more effective, therapeutic peptides.
Therapeutic peptides currently represent about 10% of marketed drugs, due to their remarkable target selectivity, high sequence flexibility and low toxicity. As these peptides are sensitive to enzymatic proteolysis, unnatural modifications are introduced to improve their stability, structural conformation and bioavailability. The immunogenicity* of therapeutic peptides is a critical issue for their development and safe use in humans. Anti-peptide antibodies produced by patients following injections of therapeutic peptides may alter their pharmacokinetics, compromise their therapeutic efficacy or cause autoimmune or allergic symptoms. However, the effects on immunogenicity of most unnatural modifications introduced into therapeutic peptides have rarely been studied. In this work, researchers evaluated the effects of introducing six common unnatural modifications to a highly immunogenic test peptide (influenza hemagglutinin (HA)** peptide) on its ability to elicit an immune response by measuring the stimulation of human CD4 T-cells, at the origin of immune responses. They thus were able to observe the effect of introducing D-amino acids (Daa), amino isobutyric acid (Aib), N-methylation, Cα-methylation, amino bond reduction, and peptoid bonds into this peptide (Figure) and showed a wide range of responses for the 69 analogues studied, many of which resulted in a substantial loss of response.
By exhaustively analyzing the impact of six unnatural modifications widely used to design therapeutic peptides on the induction of an immune response, the researchers showed, on one hand, that these modifications did not lead to an increased response and, on the other hand, that they significantly decreased the activation of T-cells (CD4 lymphocytes). These data provide important clues to the appropriate use of unnatural modifications to minimize the immunogenicity of therapeutic peptides.Contact: Bernard Maillère *Immunogenicity: A molecule is said to be immunogenic when it is capable of inducing an immune response which is mainly expressed by the appearance of antibodies directed against itself. **HA (hemagglutinin) is an immunogenic glycoprotein found on the surface of the influenza virus.
A. Azam, S. Mallart, S. Illiano, O. Duclos, C. Prades and B. Maillère. Introduction of Non-natural Amino Acids Into T-Cell Epitopes to Mitigate Peptide-Specific T-Cell Responses. Front Immunol. 2021 ; 12:637963 https://doi.org/10.3389/fimmu.2021.637963
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