Peptidomimetic nitrile inhibitors of malarial protease falcipain-2 with high selectivity against human cathepsins

被引:20
作者
Nizi, Emanuela [1 ]
Sferrazza, Alessio [1 ]
Fabbrini, Danilo [1 ]
Nardi, Valentina [1 ]
Andreini, Matteo [1 ]
Graziani, Rita [2 ]
Gennari, Nadia [2 ]
Bresciani, Alberto [2 ]
Paonessa, Giacomo [2 ]
Harper, Steven [1 ]
机构
[1] IRBM Sci Pk, Dept Chem, Via Pontina Km 30,600, I-00071 Rome, Italy
[2] IRBM Sci Pk, Dept Biol, Via Pontina Km 30,600, I-00071 Rome, Italy
关键词
Malaria; Falcipain-2; Peptidomimetic-nitrile; 3-Pyridine; Selective;
D O I
10.1016/j.bmcl.2018.03.069
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Falcipain-2 (FP2) is an essential enzyme in the lifecycle of malaria parasites such as Plasmodium falciparum, and its inhibition is viewed as an attractive mechanism of action for new anti-malarial agents. Selective inhibition of FP2 with respect to a family of human cysteine proteases (that include cathepsins B, K, L and S) is likely to be required for the development of agents targeting FP2. Here we describe a series of P2-modified aminonitrile based inhibitors of FP2 that provide a clear strategy toward addressing selectivity for the P. falciparum and show that it can provide potent FP2 inhibitors with strong selectivity against all four of these human cathepsin isoforms. (C) 2018 Elsevier Ltd. All rights reserved.
引用
收藏
页码:1540 / 1544
页数:5
相关论文
共 12 条
[1]   Mining a Cathepsin Inhibitor Library for New Antiparasitic Drug Leads [J].
Ang, Kenny K. H. ;
Ratnam, Joseline ;
Gut, Jiri ;
Legac, Jennifer ;
Hansell, Elizabeth ;
Mackey, Zachary B. ;
Skrzypczynska, Katarzyna M. ;
Debnath, Anjan ;
Engel, Juan C. ;
Rosenthal, Philip J. ;
McKerrow, James H. ;
Arkin, Michelle R. ;
Renslo, Adam R. .
PLOS NEGLECTED TROPICAL DISEASES, 2011, 5 (05)
[2]  
Beaulieu C, 2008, BIOORGAN MED CHEM, V20, P7444
[3]   Falcipain Inhibitors: Optimization Studies of the 2-Pyrimidinecarbonitrile Lead Series [J].
Coteron, Jose M. ;
Catterick, David ;
Castro, Julia ;
Chaparro, Maria J. ;
Diaz, Beatriz ;
Fernandez, Esther ;
Ferrer, Santiago ;
Gamo, Francisco J. ;
Gordo, Mariola ;
Gut, Jiri ;
de las Heras, Laura ;
Legac, Jennifer ;
Marco, Maria ;
Miguel, Juan ;
Munoz, Vicente ;
Porras, Esther ;
de la Rosa, Juan C. ;
Ruiz, Jose R. ;
Sandoval, Elena ;
Ventosa, Pilar ;
Rosenthal, Philip J. ;
Fiandor, Jose M. .
JOURNAL OF MEDICINAL CHEMISTRY, 2010, 53 (16) :6129-6152
[4]   Peptidomimetic nitriles as selective inhibitors for the malarial cysteine protease falcipain-2 [J].
Ehmke, Veronika ;
Kilchmann, Falco ;
Heindl, Cornelia ;
Cui, Kunqiang ;
Huang, Jin ;
Schirmeister, Tanja ;
Diederich, Francois .
MEDCHEMCOMM, 2011, 2 (08) :800-804
[5]   Falcipain-2 Inhibitors [J].
Ettari, Roberta ;
Bova, Floriana ;
Zappala, Maria ;
Grasso, Silvana ;
Micale, Nicola .
MEDICINAL RESEARCH REVIEWS, 2010, 30 (01) :136-167
[6]   The discovery of odanacatib (MK-0822), a selective inhibitor of cathepsin K [J].
Gauthier, Jacques Yves ;
Chauret, Nathalie ;
Cromlish, Wanda ;
Desmarais, Sylvie ;
Duong, Le T. ;
Falgueyret, Jean-Pierre ;
Kimmel, Donald B. ;
Lamontagne, Sonia ;
Leger, Serge ;
LeRiche, Tammy ;
Li, Chun Sing ;
Masse, Frederic ;
Mckay, Daniel J. ;
Nicoll-Griffith, Deborah A. ;
Oballa, Renata A. ;
Palmer, James T. ;
Percival, M. David ;
Riendeau, Denis ;
Robichaud, Joel ;
Rodan, Gideon A. ;
Rodan, Sevgi B. ;
Seto, Carmai ;
Therien, Michel ;
Truong, Vouy-Linh ;
Venuti, Michael C. ;
Wesolowski, Gregg ;
Young, Robert N. ;
Zamboni, Robert ;
Black, W. Cameron .
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2008, 18 (03) :923-928
[7]   Structural and functional characterization of falcipain-2, a hemoglobinase from the malarial parasite Plasmodium falciparum [J].
Hogg, Tanis ;
Nagarajan, Krishna ;
Herzberg, Saskia ;
Chen, Lili ;
Shen, Xu ;
Jiang, Hualiang ;
Wecke, Maria ;
Blohmke, Christoph ;
Hilgenfeld, Rolf ;
Schmidt, Christian L. .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2006, 281 (35) :25425-25437
[8]   Structures of Falcipain-2 and Falcipain-3 Bound to Small Molecule Inhibitors: Implications for Substrate Specificity [J].
Kerr, Lain D. ;
Lee, Ji H. ;
Pandey, Kailash C. ;
Harrison, Amanda ;
Sajid, Mohammed ;
Rosenthal, Philip J. ;
Brinen, Linda S. .
JOURNAL OF MEDICINAL CHEMISTRY, 2009, 52 (03) :852-857
[9]   Analysis of non-peptidic compounds as potential malarial inhibitors against Plasmodial cysteine proteases via integrated virtual screening workflow [J].
Musyoka, Thommas M. ;
Kanzi, Aquillah M. ;
Lobb, Kevin A. ;
Bishop, Ozlem Tastan .
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS, 2016, 34 (10) :2084-2101
[10]   Discovery of a Selective Series of Inhibitors of Plasmodium falciparum HDACs [J].
Ontoria, Jesus M. ;
Paonessa, Giacomo ;
Ponzi, Simona ;
Ferrigno, Federica ;
Nizi, Emanuela ;
Biancofiore, Ilaria ;
Malancona, Savina ;
Graziani, Rita ;
Roberts, David ;
Willis, Paul ;
Bresciani, Alberto ;
Gennari, Nadia ;
Cecchetti, Ottavia ;
Monteagudo, Edith ;
Orsale, Maria V. ;
Veneziano, Maria ;
Di Marco, Annalise ;
Cellucci, Antonella ;
Laufer, Ralph ;
Altamura, Sergio ;
Summa, Vincenzo ;
Harper, Steven .
ACS MEDICINAL CHEMISTRY LETTERS, 2016, 7 (05) :454-459