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Toxins, transport and therapeutic innovation

​We develop broad-spectrum inhibitors of bacterial toxins that interfere with the intracellular trafficking machinery. As a result, these inhibitors have also antiviral, anti-intracellular bacteria and anti-parasitic activities. We also develop a fragment of the diphtheria toxin as an inhibitor of HB-EGF for the treatment of rapidly progressive glomerulonephritis, a rare kidney disease.

Published on 29 April 2022


​TEAM LEADER

Julien BARBIER 

Julien.barbier@cea.fr



The Toxins, transport and therapeutic innovation group is involved in two main research topics.


​DEVELOPMENT OF BROAD-SPECTRUM INHIBITORS OF PATHOGEN AGENTS

We develop several families of molecules blocking intracellularly-acting plant and bacterial toxins. These molecules act as broad-spectrum inhibitors of toxins and various pathogens that use intracellular trafficking pathways to invade cells. As a result, these inhibitors have also antiviral, anti-intracellular bacteria and anti-parasitic activities. These inhibitors were discovered since 2010: Retro-1, Retro-2, ABMA and C910 (Stechmann et al., 2010; Wu et al., 2017; Wu et al., 2021). Since 2013, for each of them, we have:

  • Optimized molecules up to nM EC50s on a chosen target pathogen (Table A) (Noël et al., 2013; Gupta et al., Gupta et al., 2017; Wu et al., 2019; Abdelkafi et al., 2020),
  • Extended the range of sensitive toxins and pathogens up to in vivo mouse POC (Table B) (Stechmann et al., 2010; Secher et al., 2015; Harrison et al., 2016; Gupta et al., 2017; Wu et al., 2017; Dai et al., 2017; Dai et al., 2018; Shtanko et al., 2018; Wu et al., 2021),
  • Progressed into mechanism of action (ABMA, Wu et al., 2017; 2020), (C910, Wu et al., 2021) and target identification (Retro-2, Forrester et al., 2020)
  • Pursued preclinical development with pharmacokinetics and ADME studies.


​DESIGN OF A POWERFUL INHIBITOR OF HB-EGF FOR THE TREATMENT OF RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS

Rapidly progressive glomerulonephritis is a rare kidney disease in which the filtration units of the kidneys, the glomeruli, are irretrievably destroyed. The disease is due to an (auto)-immune aggression of the glomeruli involving autoantibodies or antibacterial antibodies. The immune aggression activates the expression of a growth factor, HB-EGF, by podocytes, the specialized cells forming the filtration barrier of the kidney. As a result, the podocytes and glomerular parietal cells dedifferentiate and proliferate, destroying the glomeruli. Blocking HB-EGF protect the glomeruli despite the persistence of autoantibodies. Current treatments are based solely on immunosuppression and do no protect the kidney from HB-EGF. As a consequence, the disease is poorly managed leading to a high requency of terminal kidney failure or death.

The membrane precursor form of HB-EGF is also the natural receptor for the diphtheria toxin. Thus, we engineered, from a fragment of the diphtheria toxin, a powerful inhibitor of HB-EGF called DTR8, capable of blocking the proliferation of podocytes.

An initial proof of concept study in an animal model of the disease showed that DTR8 can protect the glomeruli and prevent kidney failure. Our goal is now to turn DTR8 into a drug for the treatment of rapidly progressive glomerulonephritis.