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Discovery of Potent, Selective and Reversible Caspase-3 Inhibitors

合成化学 2004年第Z1期12卷 13-13页

作者： André Giroux john colucci Christopher I. Bayly Daniel J. Mckay Sophie Roy Steve Xanthoudakis john Vaillancourt Dita M. Rasper john Tam Paul Tawa Donald W. Nicholson Robert J. Zamboni Department of Medicinal Chemistry Department of Biochemistry and Molecular Biology Merck Frosst Centre for Therapeutic Research Merck Frosst Canada & Co. P.O. Box 1005 Pointe-Claire-DorvalQuebec Canada H9R 4P8

Recent studies towards understanding the molecular mechanisms of apoptosis have revealed the importance of a group of cysteinyl aspartate specific proteases, the caspases, in the programmed cell death process (Hengartner, M.O. Nature 2000, 407, 770). Caspase-3, in particular,has been characterized as the dominant effector caspase involved in the proteolytic cleavage of a variety of protein substrates including cytoskeletal proteins, kinases and DNA repair enzymes during apoptosis (Nicholson, D. W. Cell Death Differ. 1999, 6, 1028). The development of potent and selective caspase-3 inhibitors has thus emerged as an attractive therapeutic target. In the presentation,the identification of a series of potent, selective and reversible non-peptidyl caspase-3 inhibitors containing a pyrazinone core (1) will be presented. SAR optimization at R1, R2, R3 and R4 led to the discovery of inhibitors such as 2 with excellent in vitro activities (IC50 against rh-caspase-3: 5 nM; IC50 against camptothecin induced apoptotic cell death in NT2 cells: 20 nM). Compounds such as 2 also displayed excellent in vivo activities in a number of animal models of acute injuries (see: Methot, N. et al, J. Exp. Med. 2004, 119, 199; Toulmond, S. et al, British J. Pharm. 2004, 141,689; Holtzman,D.M. et al, JBC, 2002, 277, 30128), and selected examples will be discussed during the presentation.

关键词： programmed cell death cytoskeletal proteins molecular mechanisms identification of animal models DNA repair in vitro

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Variations in killer-cell immunoglobulin-like receptor and human leukocyte antigen genes and immunity to malaria

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Cellular & Molecular Immunology 2020年第8期17卷 799-806页

作者： Stephen Tukwasibwe Annettee Nakimuli James Traherne Olympe Chazara Jyothi Jayaraman john Trowsdale Ashley Moffett Prasanna Jagannathan Philip JRosenthal Stephen Cose Francesco colucci Makerere University KampalaUganda University of Cambridge CambridgeUK University of Cambridge Centre for Trophoblast Research CambridgeUK School of Medicine Stanford UniversityStanfordCAUSA University of California San FranciscoCAUSA MRC/UVRI and LSHTM Uganda Research Unit KampalaUganda Department of Obstetrics&Gynaecology National Institute for Health Research Cambridge Biomedical Research CentreUniversity of CambridgeCambridgeCB20SWUK

Malaria is one of the deadliest infectious diseases in the world. Immune responses to Plasmodium falciparum malaria vary among individuals and between populations. Human genetic variation in immune system genes is likely to play a role in this heterogeneity. Natural killer (NK) cells produce inflammatory cytokines in response to malaria infection, kill intraerythrocytic Plasmodium falciparum parasites by cytolysis, and participate in the initiation and development of adaptive immune responses to plasmodial infection. These functions are modulated by interactions between killer-cell immunoglobulin-like receptors (KIRs) and human leukocyte antigens (HLAs). Therefore, variations in KIR and HLA genes can have a direct impact on NK cell functions. Understanding the role of KIRs and HLAs in immunity to malaria can help to better characterize antimalarial immune responses. In this review, we summarize the different KIRs and HLAs associated with immunity to malaria thus far.

关键词： Genetic variation Human Leukocyte Antigen Innate immunity Killer-cell immunoglobulin-like receptor Malaria Natural killer cells

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