Homotrimerization Approach in the Design of Thrombospondin-1 Mimetic Peptides with Improved Potency in Triggering Regulated Cell Death of Cancer Cells.

Autor:	Denèfle T; Sorbonne Université , Ecole Normale Supérieure, PSL University, CNRS, Laboratoire des Biomolécules, LBM , 75005 Paris , France.; Sorbonne Université , Ecole Normale Supérieure, PSL University, CNRS, Laboratoire des Biomolécules, LBM, Site OncoDesign , 25-27 Avenue du Québec , 91140 Les Ulis , France., Pramil E; Sorbonne Université , Ecole Normale Supérieure, PSL University, CNRS, Laboratoire des Biomolécules, LBM , 75005 Paris , France.; Sorbonne Université , Ecole Normale Supérieure, PSL University, CNRS, Laboratoire des Biomolécules, LBM, Site OncoDesign , 25-27 Avenue du Québec , 91140 Les Ulis , France.; Cell Death and Drug Resistance in Lymphoproliferative Disorders Team , Centre de Recherche des Cordeliers, INSERM UMRS 1138 , 75006 Paris , France., Gómez-Morales L; Sorbonne Université , Ecole Normale Supérieure, PSL University, CNRS, Laboratoire des Biomolécules, LBM , 75005 Paris , France.; Sorbonne Université , Ecole Normale Supérieure, PSL University, CNRS, Laboratoire des Biomolécules, LBM, Site OncoDesign , 25-27 Avenue du Québec , 91140 Les Ulis , France.; Laboratory of Immunology and Virology , Autonomous University of Nuevo Leon , 66451 San Nicolas de los Garza , NL , Mexico., Levasseur MD; Sorbonne Université , Ecole Normale Supérieure, PSL University, CNRS, Laboratoire des Biomolécules, LBM , 75005 Paris , France.; Sorbonne Université , Ecole Normale Supérieure, PSL University, CNRS, Laboratoire des Biomolécules, LBM, Site OncoDesign , 25-27 Avenue du Québec , 91140 Les Ulis , France., Lardé E; Sorbonne Université , Ecole Normale Supérieure, PSL University, CNRS, Laboratoire des Biomolécules, LBM , 75005 Paris , France.; Sorbonne Université , Ecole Normale Supérieure, PSL University, CNRS, Laboratoire des Biomolécules, LBM, Site OncoDesign , 25-27 Avenue du Québec , 91140 Les Ulis , France., Newton C; Sorbonne Université , Ecole Normale Supérieure, PSL University, CNRS, Laboratoire des Biomolécules, LBM , 75005 Paris , France.; Sorbonne Université , Ecole Normale Supérieure, PSL University, CNRS, Laboratoire des Biomolécules, LBM, Site OncoDesign , 25-27 Avenue du Québec , 91140 Les Ulis , France., Herry K; OncoDesign , 25 Avenue du Québec , 91140 Les Ulis , France., Herbi L; Cell Death and Drug Resistance in Lymphoproliferative Disorders Team , Centre de Recherche des Cordeliers, INSERM UMRS 1138 , 75006 Paris , France., Lamotte Y; OncoDesign , 25 Avenue du Québec , 91140 Les Ulis , France., Odile E; Sorbonne Université , Ecole Normale Supérieure, PSL University, CNRS, Laboratoire des Biomolécules, LBM , 75005 Paris , France.; Sorbonne Université , Ecole Normale Supérieure, PSL University, CNRS, Laboratoire des Biomolécules, LBM, Site OncoDesign , 25-27 Avenue du Québec , 91140 Les Ulis , France., Ancellin N; OncoDesign , 25 Avenue du Québec , 91140 Les Ulis , France., Grondin P; OncoDesign , 25 Avenue du Québec , 91140 Les Ulis , France., Martinez-Torres AC; Laboratory of Immunology and Virology , Autonomous University of Nuevo Leon , 66451 San Nicolas de los Garza , NL , Mexico., Viviani F; OncoDesign , 25 Avenue du Québec , 91140 Les Ulis , France., Merle-Beral H; Cell Death and Drug Resistance in Lymphoproliferative Disorders Team , Centre de Recherche des Cordeliers, INSERM UMRS 1138 , 75006 Paris , France., Lequin O; Sorbonne Université , Ecole Normale Supérieure, PSL University, CNRS, Laboratoire des Biomolécules, LBM , 75005 Paris , France., Susin SA; Cell Death and Drug Resistance in Lymphoproliferative Disorders Team , Centre de Recherche des Cordeliers, INSERM UMRS 1138 , 75006 Paris , France., Karoyan P; Sorbonne Université , Ecole Normale Supérieure, PSL University, CNRS, Laboratoire des Biomolécules, LBM , 75005 Paris , France.; Sorbonne Université , Ecole Normale Supérieure, PSL University, CNRS, Laboratoire des Biomolécules, LBM, Site OncoDesign , 25-27 Avenue du Québec , 91140 Les Ulis , France.; SiRIC CURAMUS (CANCER UNITED RESEARCH ASSOCIATING MEDICINE, UNIVERSITY & SOCIETY, Site de Recherche Intégrée sur le Cancer) IUC, AP-HP.6 , Sorbonne Université 75005 Paris , France.; Kayvisa AG , Industriestrasse, 44 , 6300 Zug , Switzerland.; Kaybiotix GmbH , Zugerstrasse 32 , 6340 Baar , Switzerland.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2019 Sep 12; Vol. 62 (17), pp. 7656-7668. Date of Electronic Publication: 2019 Aug 26.
DOI:	10.1021/acs.jmedchem.9b00024
Abstrakt:	In order to optimize the potency of the first serum-stable peptide agonist of CD47 (PKHB1) in triggering regulated cell death of cancer cells, we designed a maturation process aimed to mimic the trimeric structure of the thrombospondin-1/CD47 binding epitope. For that purpose, an N-methylation scan of the PKHB1 sequence was realized to prevent peptide aggregation. Structural and pharmacological analyses were conducted in order to assess the conformational impact of these chemical modifications on the backbone structure and the biological activity. This structure-activity relationship study led to the discovery of a highly soluble N-methylated peptide that we termed PKT16. Afterward, this monomer was used for the design of a homotrimeric peptide mimic that we termed [PKT16] 3 , which proved to be 10-fold more potent than its monomeric counterpart. A pharmacological evaluation of [PKT16] 3 in inducing cell death of adherent (A549) and nonadherent (MEC-1) cancer cell lines was also performed.
Databáze:	MEDLINE
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