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Home > Teams > Fluorinated Molecules and Peptides of Therapeutic Interest - FLUOPEPIT

Fluorinated Molecules and Peptides of Therapeutic Interest - FLUOPEPIT

The research pursued in our group focuses on new synthetic methodologies, involving organofluorine and peptide chemistry, devoted to medicinal chemistry and effort towards new processes respectful of environment. The group has a long lasting experience in biologically active molecules where the introduction of fluoroalkyl substituents can improve the pharmacological profile of drugs. Typical examples are fluorinated peptidomimetics and analogs of natural products: artemisinin derivatives (anti-malaria and anti-cancer) and styryl lactone analogs (anti-tumor). Our group has also a long experience in the peptidomimetic units design and synthesis as inhibitors of protein-protein interactions: anti-infectious (anti HIV), anti-tumor drugs (proteasome) and inhibition of amyloide aggregation. Here are depicted the main research thematics of the group:


Directors

Pr. S. Ongeri and Dr. B. Crousse


Expertises area

  • anti-Alzheimer’s agents (mimics of β-strands and β-sheets, β-sheet breakers)
  • anti-tumor agents (proteasome inhibitors)
  • anti-infectious agents (HIV-1 protease, cabapenemase inhibitors)
  • Protein-protein interaction
  • Fluorine chemistry, fluorous phase
  • Peptidic and peptidomimetic synthesis


Collaborations

  • UMR 8612, University Paris Sud, France: Pr. M. Taverna (capillary electrophoresis)
  • P. & M. Curie University, Paris, France: Pr. Lequin, Dr. Khemtemourian (NMR conformational studies, fluorescence spectroscopy, CD)
  • University Insubria and Università degli Studi di Milano, Italy (Pr. Piarulli, Pr. Gennari, Pr. Gelmi)
  • Central Glass Ltd, Japan (fluorinated reagents)
  • Tosoh Ltd, Japan (fluorinated reagents)
  • Fiocruz, Rio de Janeiro, Brazil (natural products, medicinal chemistry)


Permanent people


Students/Post-docs/Non permanent people:

  • N. Bisi - Ph D. Student
  • L. Bodero - Post-Doc
  • T-T. Cao - Ph D. Student
  • M. Delaunay- Ph D. Student
  • D. Di Lorenzo - PhD. Student
  • P. Gao - Ph D. Student
  • J. Laxio Arenas - Ph D. Student
  • L. Radal - Post-Doc
  • C. Shi - Ph D. Student
  • M. Skibinska - Ph D. Student


EUROPEAN NETWORKS - FETOPEN "No Pest"

The FETOPEN project "NoPEST", started in January 2019, aims to find alternatives to copper salts massively used against oomycetes responsible in particular for downy mildew...

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Amyloid protein aggregation inhibitors

- Comprehensive understanding of the aggregation process of amyloid proteins : Aβ1-42 involved in Alzheimer’s disease and hIAPP involved in type II Diabetes
- Inhibition of the aggregation process by the design of small peptides and peptidomimetics
- Discovery of selective diagnostic tools to detect toxic soluble species of amyloid proteins

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Fluorinated building blocks

Fluorine has become a fundamental tool in the development of drugs. Trifluoromethylated compounds are particularly important, as shown by the number of CF3-containing drugs and drug-candidates in clinical use or in development.

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Fluorous phase, fluorinated alcohols

Fluoroalkyl alcohols TFE and HFIP possessed particular properties (acidity, polarity, high H-Bond donor, …), and allowed to perform clean and selective reactions without external promotor (Lewis acid, or Brönsted acid).

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Molecular modelling

The goal of the “molecular modelling” team is to support rational design of new compounds targetting biological molecules and complexes, using various up-to-date in silico techniques, including quantum molecular calculations, all-atom molecular dynamics simulations, and coarse-grained modelling.

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Publications

  1. Introducing sequential aza-amino acids units induces repeated β-turns and helical conformations in peptides.; N. Tonali, I. Correia, J. Lesma, G. Bernadat, S. Ongeri and O. Lequin.
    - Org. Biomol. Chem., 2020, 18, 3452.
  2. Real‐time BODIPY‐binding assay to screen inhibitors of the early oligomerization process of Aβ 1‐42 peptide; N. Tonali, V. I. Dodero, J. Kaffy, L. Hericks, S. Ongeri, N. Sewald.
    - ChemBioChem 2020, 21, 1129.
  3. Evidence for different in vitro oligomerization behavior of synthetic hIAPP obtained from different sources; C. Berardet, J. Kaffy, F. Halgand, G. Van der Rest, S. Ongeri, M. Taverna.
    - Analytical and Bioanalytical Chemistry 2020, 412, 3103.
  4. Direct Access to Substituted 4-CF3 β-Lactams in C-3 Position.; M. Skibińska, M. Kaźmierczak, T. Milcent, T. Cytlak, H. Koroniak and B. Crousse.
    - Frontiers Organic Chemistry, 2019, Vol 7, Article 526. Special issue: Research Topic: Strained Aza-Heterocycles in Synthesis.

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A Cover paper

A major current issue in medicinal chemistry is the design of small peptide analogues resistant to proteolysis and able to adopt preferential conformations, while preserving the selectivity and efficiency of natural peptides. Whereas the introduction of one aza-Gly in peptides has proven numerous biological and structural interest, the conformational effect of sequential aza-Gly or azaamino acids bearing side chains has not been investigated. In this work, experimental NMR and X-ray data together with in silico conformational studies reveal that the introduction of two consecutive aza-amino acids in pseudotripeptides induces the formation
of stable hydrogen-bonded β-turn structures. Notably, this stabilization effect relies on the presence of side chains on aza-amino acids, as more flexible conformations are observed with aza-Gly residues. Remarkably, a longer aza/aza/α/aza/aza/α pseudohexapeptide containing substituted aza-amino acids adopts repeated β-turns conformations which interconvert with a fully helical structure mimicking a 310 helix.
Introducing sequential aza-amino acids units induces repeated β-turns and helical conformations in peptides
Nicolo Tonali, Isabelle Correia, Jacopo Lesma, Guillaume Bernadat,
Sandrine Ongeri and Olivier Lequin Org. Biomol. Chem 2020,
18, 3452.
https://doi.org/10.1039/C9OB02654A

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Bioorganic and Medicinal Chemistry of Fluorine (Book)
J.-P. Bégué et D. Bonnet-Delpon

Edition - June 2008
72.90 Euro
2008. 366 Pages, Hardcover
ISBN-10: 0-470-27830-7
ISBN-13: 978-0-470-27830-7 - John Wiley & Sons

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