Research AND COLLABORATIVE PROJECTS

Antimicrobial peptides

Tens of thousands of different antimicrobial peptides (AMPs) have been identified in different living species, displaying a wide range of activities including antibacterial, antifungal and antiparasitic. In the light of the priorities listed by the World Health Organisation, we have studied the mechanism of action of peptides acting on ESKAPE bacteria.

Bombinin-like-3 peptide from from Xenopus skin acts on Neisseria, Pseudomonas aeruginosa, and Staphylococcus aureus while the synthetic K11 peptide inspired by cecropin A1, melittin and magainin acts on Acinetobacter baumannii, methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa, Staphylococcus epidermidis, and Klebsiella pneumoniae.

Most AMPs interact with the membrane of their target organism whose composition can be modeled by phospholipid vesicles to be studied by Nulear Magnetic resoannce (NMR) or by Molecular Dynamics (MD) simulations.

MD snapshots of K11 antilicrobial peptide interacting with phospholipid bilayers mimicking bacterial membranes.

Ramos-Martín F, Herrera-León C, Antonietti V, Sonnet P, Sarazin C, D’Amelio N. Antimicrobial Peptide K11 Selectively Recognizes Bacterial Biomimetic Membranes and Acts by Twisting Their Bilayers. Pharmaceuticals . 2020;14. doi:10.3390/ph14010001

Annaval T, Ramos-Martín F, Herrera-León C, Adélaïde M, Antonietti V, Buchoux S, et al. Antimicrobial Bombinin-like Peptide 3 Selectively Recognizes and Inserts into Bacterial Biomimetic Bilayers in Multiple Steps. J Med Chem. 2021;64: 5185–5197. doi:10.1021/acs.jmedchem.1c00310

Anticancer peptides

Many antimicrobial peptides display significant anticancer properties which promise to overcome the main limitations of conventional anticancer drugs: lack of selectivity and resistance. The positive charge of cationic anticancer peptides (ACPs) drives them selectively towards cancer cells. As opposed to the essentially uncharged human cell membranes, cancer cell membranes tend to be more negatively charged because of a large amount of sialic acid-rich glycoproteins, phosphatidylserine (PS) or heparan sulfate. They are also more fluid, due to a reduced presence of cholesterol impeding the entrance of ACPs. Although exceptions exist, ACPs are less prone to induce resistance due to the complexity and heterogeneity of the cellular membrane as compared to a single molecular target.

In our laboratories we have studied the mechanism of action of different cecropins (XJ, A and D) from Bombyx mori. These peptides are able to penetrate in cancer cells and target their mitochondria leading to apoptosis. Their cell penetrating properties can be exploited to transport conjugate conventional drugs to intracellular targets (conjugates).

Some cecropins induce apoptosis in cancer cells by bypassing the plasmic membrane and interacting with the membrane of their mitochondria. Image created by Biorender.

Ramos-Martín F, D’Amelio N. Molecular Basis of the Anticancer and Antibacterial Properties of CecropinXJ Peptide: An In Silico Study. Int J Mol Sci. 2021;22. doi:10.3390/ijms22020691

Ramos-Martín F, Herrera-León C, D’Amelio N. Bombyx mori Cecropin D could trigger cancer cell apoptosis by interacting with mitochondrial cardiolipin. Biochim Biophys Acta Biomembr. 2022;1864: 184003. doi:10.1016/j.bbamem.2022.184003

Herrera-León C, Ramos-Martín F, Antonietti V, Sonnet P, D’Amelio N. The impact of phosphatidylserine exposure on cancer cell membranes on the activity of the anticancer peptide HB43. FEBS J. 2021. doi:10.1111/febs.16276

ADAPTABLE web-server

We developed the ADAPTABLE web platform as a tool for researchers studying AMPs. It introduces the concept of "property alignment" to create families of property- and sequence-related peptides (SR families). This allows researchers to select AMPs that are meaningful to their research from among more than 40,000 nonredundant sequences. Selectable properties include the target organism and experimental activity concentration. This means that researchers can select peptides with multiple simultaneous actions. ADAPTABLE is able to do this because it not only merges sequences of AMP databases, but also merges their data. This standardization of values and handling of non-proteinogenic amino acids makes ADAPTABLE a powerful tool for studying AMPs.

Ramos-Martín F, Annaval T, Buchoux S, Sarazin C, D’Amelio N. ADAPTABLE: a comprehensive web platform of antimicrobial peptides tailored to the user’s research. Life Sci Alliance. 2019;2. doi:10.26508/lsa.201900512

ADAPTABLE web platform

Peptides as drug enhancers

Due to their capability of disrupting the architecture of biological membranes, AMPs can be used to enhance the action of conventional antibiotics in cases where the resistance is created by reduced access to bacterial intracellular targets. SAAP-148 and Cathelicidin-BF from frog skin were selected for their low hemolytic properties and studied within the consortium of the French-German NATURAL-ARSENAL project funded by ANR and BMBF national agencies.

Adélaïde M, Salnikov E, Ramos-Martín F, Aisenbrey C, Sarazin C, Bechinger B, et al. The Mechanism of Action of SAAP-148 Antimicrobial Peptide as Studied with NMR and Molecular Dynamics Simulations. Pharmaceutics. 2023;15. doi:10.3390/pharmaceutics15030761

NATURAL-ARSENAL project

Eliciting peptides

In plants, peptides can induce defence signalling through their perception by a receptor or by interacting with the target membrane. In collaboration with the group of Dr. Sébastien Aubourg at Institut de Recherche en Horticulture et Semences, of the University of Angers (INRAE), we study secreted pro-peptides derived from the Arabidopsis PROSCOOP genes, which undergo maturation to produce peptides named SCOOP. Although they are not structured in solution, their residual structure might be stabilized when interacting with their target.

Guillou M-C, Balliau T, Vergne E, Canut H, Chourré J, Herrera-León C, et al. The PROSCOOP10 Gene Encodes Two Extracellular Hydroxylated Peptides and Impacts Flowering Time in Arabidopsis. Plants. 2022;11. doi:10.3390/plants11243554

NMR of Antimicrobial peptides in living bacteria

In collaboration with the group of Frances Separovic at the Bio21 lab, University of Melbourne we are studying the interaction of the anticancer peptide HB43 in living bacteria thanks to the expertise of Dr. Marc-Antoine Sani in the use of DNP-NMR. These preliminary studies have been supported by the S2R funding scheme of UPJV and by FASIC.

DNP image from Rosay M et al.,Journal of Magnetic Resonance, 264,2016, 88-98,https://doi.org/10.1016/j.jmr.2015.12.026

Peptide expressing probiotics

In collaboration with Luis Bermudez (DR INRAE) leading the group Probiotic, Commensals and Inflammation in the team ProbiHôte (headed by P. Langella) at MICALIS Institute, we are engineering probiotics for the in-situ expression of antimicrobial and anticancer peptides.

The antimicrobial activity of intrinsically disordered proteins involved in neurodegeneration

In collaboration with Pr. Mariapina D'Onofrio at the University of Verona we are studying the interaction tau protein and synuclein, two proteins involved in Alzheimer and Parkinson diseases, with models of bacterial and eukaryotic membranes. Intrinsically disordered proteins have much in common with antimicrobial peptides and might have antibacterial roles in the brain. These preliminary studies have been supported by the S2R funding scheme of UPJV.

Bypassing the blood-brain barrier with anti-amylodoigenic QBP1 peptide

In collaboration with the group of Pascal Sonnet at UPJV and Fabien Gosselet of Artois University, we are designing antimicrobial peptides able to bypass the blood-brain barrier and carry the anti-amyloidogenic peptide QBP1 which has been shown to inhibit the aggregation of proteins involved in neurodegeneration. The project is funded by the MOSOPS project (Projet MOSOPS - Modélisation, Simulation, Optimisation des impacts, des Soins et des Parcours de Santé) presented in collaboration among UPJV, University of Artois and University of Littoral Côte d'Opale and funded within the frame of the CPER 2021-2027 (Contrat Contrat de Plan Etat-Région).

Developing novel molecular simulation, analysis and prediction methods

Biomacromolecules, including membranes, proteins and peptides, recognize each other and operate their biological functions via the collective correlated motion of their constitutive atoms, which trigger complex conformational transitions. The timescales of these transitions (milliseconds and longer) makes them difficult to simulate on state-of-the-art computer hardware using traditional molecular simulation methods. We use and develop enhanced sampling simulation methods to accelerate these transitions to shorter timescales while limiting the imposed bias. We combine them with coarse-grained methods which replace atoms by a smaller number of pseudoparticles, further reducing computational cost. Finally, as an alternative to costly simulations, we use machine learning (in particular deep learning) to predict the properties of given biomolecular systems from their sequences or chemical nature -- or conversely to suggest systems potentially possessing a desirable set of properties.

Accelerated formation of a POPE liposome using enhanced sampling simulations (Bouvier, J. Chem. Theory Comput. 15, 6551, 2019).

Recursive convolutional deep neural network, trained to predict the favorable structures of oligosaccharides from their length and chemical nature (Bouvier, J. Chem. Inf. Model. doi:10.1021/acs.jcim.3c00179, 2023).

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