Structure-Activity Relationships of JMV4463, a Vectorized Cathepsin D Inhibitor with Antiproliferative Properties: The Unique Role of the AMPA-Based Vector.

Autor: Vezenkov LL; Institut des Biomolécules Max Mousseron (IBMM), UMR5247 CNRS, Université de Montpellier, ENSCM, Faculté de Pharmacie, 15 avenue Charles Flahault, 34093, Montpellier Cedex 5, France., Sanchez CA; Institut des Biomolécules Max Mousseron (IBMM), UMR5247 CNRS, Université de Montpellier, ENSCM, Faculté de Pharmacie, 15 avenue Charles Flahault, 34093, Montpellier Cedex 5, France., Bellet V; Institut des Biomolécules Max Mousseron (IBMM), UMR5247 CNRS, Université de Montpellier, ENSCM, Faculté de Pharmacie, 15 avenue Charles Flahault, 34093, Montpellier Cedex 5, France., Martin V; Institut des Biomolécules Max Mousseron (IBMM), UMR5247 CNRS, Université de Montpellier, ENSCM, Faculté de Pharmacie, 15 avenue Charles Flahault, 34093, Montpellier Cedex 5, France., Maynadier M; Institut des Biomolécules Max Mousseron (IBMM), UMR5247 CNRS, Université de Montpellier, ENSCM, Faculté de Pharmacie, 15 avenue Charles Flahault, 34093, Montpellier Cedex 5, France., Bettache N; Institut des Biomolécules Max Mousseron (IBMM), UMR5247 CNRS, Université de Montpellier, ENSCM, Faculté de Pharmacie, 15 avenue Charles Flahault, 34093, Montpellier Cedex 5, France., Lisowski V; Institut des Biomolécules Max Mousseron (IBMM), UMR5247 CNRS, Université de Montpellier, ENSCM, Faculté de Pharmacie, 15 avenue Charles Flahault, 34093, Montpellier Cedex 5, France., Martinez J; Institut des Biomolécules Max Mousseron (IBMM), UMR5247 CNRS, Université de Montpellier, ENSCM, Faculté de Pharmacie, 15 avenue Charles Flahault, 34093, Montpellier Cedex 5, France., Garcia M; Institut des Biomolécules Max Mousseron (IBMM), UMR5247 CNRS, Université de Montpellier, ENSCM, Faculté de Pharmacie, 15 avenue Charles Flahault, 34093, Montpellier Cedex 5, France., Amblard M; Institut des Biomolécules Max Mousseron (IBMM), UMR5247 CNRS, Université de Montpellier, ENSCM, Faculté de Pharmacie, 15 avenue Charles Flahault, 34093, Montpellier Cedex 5, France., Hernandez JF; Institut des Biomolécules Max Mousseron (IBMM), UMR5247 CNRS, Université de Montpellier, ENSCM, Faculté de Pharmacie, 15 avenue Charles Flahault, 34093, Montpellier Cedex 5, France. jean-francois.hernandez@univ-montp1.fr.
Jazyk: angličtina
Zdroj: ChemMedChem [ChemMedChem] 2016 Feb 04; Vol. 11 (3), pp. 302-8. Date of Electronic Publication: 2015 Dec 07.
DOI: 10.1002/cmdc.201500457
Abstrakt: Cathepsin D (CathD) is overexpressed and secreted by several solid tumors and stimulates their growth, the mechanism of which is still not understood. In this context, the pepstatin bioconjugate JMV4463 [Ac-arg-O2 Oc-(Val)3-Sta-Ala-Sta-(AMPA)4-NH2; O2 Oc=8-amino-3,6-dioxaoctanoyl, Sta=statine, AMPA=ortho-aminomethylphenylacetyl], containing a new kind of cell-penetrating vector, was previously shown to exhibit potent antiproliferative effects in vitro and to delay the onset of tumors in vivo. In this study, we performed a structure-activity relationship analysis to evaluate the significance of the inhibitor and vector moieties of JMV4463. By modifying both statine residues of pepstatin we found that the antiproliferative activity is correlated with CathD inhibition, supporting a major role of the catalytic activity of intracellular CathD in cancer cell proliferation. Replacing the vector composed of four AMPA units with other vectors was found to abolish cytotoxicity, although all of the conjugates enabled pepstatin transport into cells. In addition, the AMPA4 vector must be localized at the C terminus of the bioconjugate. The unexpected importance of the vector structure and position for cytotoxic action suggests that AMPA4 enables pepstatin to inhibit the proteolysis of critical CathD substrates involved in cell proliferation via a unique mechanism of action.
(© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
Databáze: MEDLINE
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