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Advances in peptidomimetics as inhibitors of ABC transporters
Marie-Emmanuelle Million 1 , Ophélie Arnaud 2 , Géraldine Agusti 3 , Waël Zeinyeh 4 , Lucia Gonzalez-Lobato 2 , Ali Koubeissi 4 , Laurent Ettouati * 4 , Thierry Lomberget 4 , Joelle Paris 4 , Marc Le Borgne 4 , Pierre Falson 2
1  Université de Lyon, Université Lyon 1, Faculté de Pharmacie - ISPB, Département des Sciences du Médicament, 8 avenue Rockefeller, F-69373, Lyon Cedex 8, France
2  Equipe Labellisée Ligue 2014, BMSSI UMR 5086 CNRS/Université Lyon 1, IBCP, 69367 Lyon, France
3  Laboratoire d’Automatique et de Génie des Procédés (LAGEP), UMR-CNRS 5007, Université Claude Bernard Lyon 1, CPE Lyon, Villeurbanne Cedex, France
4  Université de Lyon, Université Lyon 1, Faculté de Pharmacie - ISPB, EA 4446 Biomolécules Cancer et Chimiorésistances, SFR Santé Lyon-Est CNRS UMS3453 - INSERM US7, 8 avenue Rockefeller, F-69373, Lyon Cedex 8, France

Published: 02 November 2015 by MDPI in 1st International Electronic Conference on Medicinal Chemistry session ECMC-1

The discovery of the physiological role of a great number of peptides (e.g. angiotensin II, neuropeptide Y, enkephalin, gonadotrophin-releasing hormone…) stimulated researchers towards design and synthesis of analogues. Since the last two decades, peptidomimetics have emerged as promising therapeutic agents such as goserelin, cetrorelix, and atazanavir. Structural modifications of the sequence of the native peptides can optimize their biological properties such as bioavailibilty, plasma half-life, resistance of metabolism and selectivity. Another advantage to develop peptidomimetics as drugs and/or probes can be the control of their conformation. A peptidomimetic with a restricted conformational flexibility can minimize binding to non-target receptors and then enhances the activity at the target receptor or transporter. Taking all together, peptidomimetics constitute a class of promising biomolecules to study ligand-protein interactions on different biological targets.

For many years, our researchers worked on multidrug resistance (MDR) to anticancer and anti-infectious agents. This phenomenon is often associated with over-expression of several proteins belonging to ABC transporters (e.g. ABCB1, ABCG2). Numerous molecules have shown activities on these transporters. Among them, we can list steroids, bivalent ligands, azaheterocycles and short linear hydrophobic peptides. For example, reversin 121, a dipeptide, showed high affinity and specificity for ABCB1.

Reversin 121 became the new starting point of our research. For 2005 we developed different series of (aza)peptidomimetic-type ligands of ABC transporters. First, we wish to expose on the synthesis work accomplished to reach our selection of molecules and secondly to present our biological data on ABCB1, and ABCG2.