ESR 1 - Alexandra Bertran

Hosted at Iproteos

ESR12 round

I obtained my Bachelor's degree in Chemistry at the University of Barcelona in Spain. Afterwards, I joined the pharmaceutical company Medichem, first in Barcelona and later in Malta. In there, I was devoted to R&D of organic synthesis, purification and analysis of chemical compounds. Then, I continued my experience in Medichem but moved to plant scale lab, where I acquired experience as a process development chemist in technology transfer from lab to pilot plant scale. I did a Master's degree in Industrial Chemistry and Introduction to Chemical Research at the Universitat Autonoma de Barcelona. In the framework of my Master's degree, I did an internship in an organic synthesis laboratory (Barcelona Science Park - PCB), focusing on solid-phase and solution peptide synthesis

Design and synthesis of selective MMP-9 inhibitors and synthesis of modulators for ADAMTS4



Background

Recent studies have unveiled the strong role of matrix metalloproteinase-9 (MMP-9) in epileptogenesis in a variety of animal models, showing an up-regulation of the protease in epileptogenic lesions. It is known that MMP-9 is involved in synaptic plasticity, learning and memory. Despite the robust evidences of the role of MMP-9 in the development and/or maintenance of epilepsy and their potential use as a therapeutic target, currently there are no selective MMP-9 inhibitors/ modulators for this metalloproteinase, which has impaired their use as clinical target. Non-selective inhibitors have been recognized to have strong side effects and toxicity thus limiting their therapeutic use.

Objectives

  • Design and synthesis of a selective MMP-9 peptide inhibitor. 
  • Demonstrate the selectivity and potency of the designed MMP-9 inhibitors over other MMP family members. 
  • Improve and refine the potency and ADME properties of the most promising MMP-9 inhibitor candidate. 
  • Validate the role of MMP-9 in epileptogenesis and epilepsy

Approach

On the basis of the crystal structure of MMP-9, combined with the proprietary technology developed by Iproteos, a structure-based drug design strategy will be used to design specific inhibitors, which may stop the catalytic activity of MMP-9 either by directly blocking its active site or through allosteric inhibition. This strategy has been already used by Iproteos to obtain highly selective and potent MMP-2 inhibitors. To achieve these objectives, the following methodology/ techniques will be used: in silico drug design, solid-phase peptide synthesis (including peptide purification, characterization and structure determination), enzymatic MMP assays, metabolic stability determination assays (blood, serum, plasma and microsomes), permeability assays across the BBB and GIT (BBB and GIT-PAMPA, Caco-2 and a BBB model based in the co-culture of brain endothelial cells and astrocytes), cytotoxicity assays (MTT test and zebrafish larvae viability), solubility determination, formulation and pharmacokinetics studies in rats.

Collaborations

For the validation of the role of MMP-9 and other ECM-related molecules in epileptogenesis and epilepsy, collaborations will be established with partners LIN (ADAMTS-4), IIT (integrin-targeting compounds), NIW and UEF. For the development of a BBB-permeable MMP-9 inhibitor, collaboration will be established with AMU and Vect-Horus.

ESR12 I obtained my Bachelor's degree in Chemistry at the University of Barcelona in Spain. Afterwards, I joined the pharmaceutical company Medichem, first in Barcelona and later in Malta. In there, I was devoted to R&D of organic synthesis, purification and analysis of chemical compounds. Then, I continued my experience in Medichem but moved to plant scale lab, where I acquired experience as a process development chemist in technology transfer from lab to pilot plant scale. I did a Master's degree in Industrial Chemistry and Introduction to Chemical Research at the Universitat Autonoma de Barcelona. In the framework of my Master's degree, I did an internship in an organic synthesis laboratory (Barcelona Science Park - PCB), focusing on solid-phase and solution peptide synthesis.

Page last modified on 05 mar 18 15:02