DS04 - Vie, santé et bien-être

Peptide supramolecular assembly as a determinant for biological function – Biosupramol

Submission summary

Histidine-rich peptides that were designed and investigated in our laboratories exhibit a large variety of biological functions that can be tuned by subtle sequence variations, pH, salt and other environmental conditions. These LAH4 peptides exhibit potent antimicrobial and pore forming activities, which are more pronounced when the histidines are charged at low pH than under neutral conditions. Furthermore, self-assembling globular complexes with nucleic acids, are very potent transfection agents when the same peptide has high cell penetrating capabilities also for other cargo. Finally, other derivatives in this peptide family exhibit excellent transduction enhancement in experiments with lenti- and adeno-associated viruses. In this project we will investigate why such subtle variations in sequence can have such profound effects on biological activities. Based on preliminary data we hypothesize that supramolecular architecture enhances small differences in sequence and ultimately determines biological functionality. Such information may be very important to determine the best usage of these adjuvants of transduction (in vitro and in vivo). Although the peptides are closely related and all made up from the same set of amino acids they can occur in mono- or small oligomeric states (antimicrobial), globular complexes in the nano- to micrometer range (transfection) or as fibrous aggregates forming hydrogels (transduction enhancement). Therefore, we propose to investigate in a systematic manner how the aggregation states in solution and in membranes correlates with their activities in antimicrobial, nucleic acid transfection and lentiviral transduction assays. Furthermore, the aggregates will be investigated by a number of highly complementary biophysical approaches including state-of-the art EM, atomic force microscopy, X-ray diffraction and solid-state NMR spectroscopy. The high resolution structural models thus developed will allow for a molecular understanding of the interactions between peptide units, between peptides and nucleic acids and between peptide complexes and membranes. In this manner it can be rationalized which amino acid residues are essential for supramolecular self-assembly, opening the path to the design of new sequences with improved characteristics for a given application. As the supramolecular assembly in aqueous environments is reversible as well as dependent on peptide concentration and chemical environment particular emphasis will be given to mimic as closely as possible the relevant conditions also in biophysical and structural investigations. Therefore, the advancement of novel solid-state NMR technologies is of utmost importance to permit the study of biomacromolecules also at low concentrations or under a restricted range of chemical environments. This problem can only be tackled through a network of 3 partners with experts in biophysics, solid-state NMR spectroscopy, cell biology and biomedical applications. In addition, through an industry-academia partnership Dynamic Nuclear Polarisation and ultra-fast MAS solid-state NMR spectroscopy will be made available, combined and further developed for this project and for biomolecular applications in general. Both technologies have been developed to boost the sensitivity of solid-state NMR experiments and to make the direct observation of 1H nuclei possible also in solid or semi solid samples. Proton-detection is of particular importance when intermolecular contact sites need to be determined, as these nuclei constitute the outermost shell of the molecules.

Project coordination

Burkhard BECHINGER (Institut de Chimie de Strasbourg)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.


CAMB Laboratoire de Conception et Application de Molécules Bioactives
UMR_S951 INTEGRARE INTEGRARE Integrated genetic approaches in therapeutic discovery for rare diseases
UNISTRA chimie Institut de Chimie de Strasbourg

Help of the ANR 500,083 euros
Beginning and duration of the scientific project: June 2018 - 36 Months

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