Poster Presentation 10th Australian Peptide Conference 2013

Intracellular delivery of Cathpesin D inhibitors by dipeptide mimetic oligomers: a target for cancer cell proliferation inhibition? (#100)

Muriel Amblard 1 , Jean-françois Hernandez 1 , Lubomir L Vezenkov 1 , Vincent Martin 1 , Marie Maynadier 1 , Marcel Garcia 1 , Jean Martinez 1
  1. Institut des Biomolécules Max Mousseron, Montpellier, France

The identification and the use of tumour progression key modulators, an overexpressed peptidase for example, constitutes a relevant approach to decrease the side toxicity of standard chemotherapies. In this work we targeted Cathepsin D (CathD), a lysosomal aspartyl protease, overexpressed and abnormally secreted by a large number of malignancies.1  This protease is involved in tumor progression and metastasis development. Moreover, several evidences involve proteolytic activity of the intracellular CathD in tumor growth and progression.2,3  Therefore, CathD inhibition represents an attractive approach for the development of potential anti-cancer agents.4  In this context, pepstatin, the most potent inhibitor of CathD so far identified has been evaluated. However, this inhibitor was showed to be inactive on cancer cell growth and this inefficiency was mainly attributed to a problem of cellular internalization. In this work, we developed cell penetrating CathD inhibitors by combining the potent pepstatin inhibitor with new vectors of cell penetration. This cell penetrating compounds were constructed by oligomerization of constrained dipeptide mimetics and they specifically targeted the endolysosomal compartment where the CathD activity is mainly localized.5,6  We showed that these conjugates were able to cross the cell membrane and  exhibited a potent anti-proliferative activity associated to the intracellular CathD proteolytic activity inhibition.

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  6. Paramelle D., Subra G., Vezenkov L. L., Maynadier M., André C., Enjalbal C., Calmès M., Garcia M., Martinez J., Amblard M., Angew. Chem. Int. Ed. Engl. 2010, 49, 8240.