Benzenesulphonamide inhibitors of the cytolytic protein perforin

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• 作者：Julie A. Spicer^a ; ^b ; ^{j.spicer@auckland.ac.nz} ; Christian K. Miller^a ; ^b ; Patrick D. O'Connor^a ; ^b ; Jiney Jose^a ; ^b ; Kristiina M. Huttunen^a ; ^c ; Jagdish K. Jaiswal^a ; ^b ; William A. Denny^a ; ^b ; Hedieh Akhlaghi^d ; Kylie A. Browne^d ; Joseph A. Trapani^d ; ^e
• 关键词：Perforin ; Perforin inhibitor ; Benzenesulphonamide ; Bioisostere ; Immunosuppressant
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2017
• 出版时间：15 February 2017
• 年：2017
• 卷：27
• 期：4
• 页码：1050-1054
• 全文大小：1018 K
• 卷排序：27

文摘

The pore-forming protein perforin is a key component of mammalian cell-mediated immunity and essential to the pathway that allows elimination of virus-infected and transformed cells. Perforin activity has also been implicated in certain auto-immune conditions and therapy-induced conditions such as allograft rejection and graft versus host disease. An inhibitor of perforin activity could be used as a highly specific immunosuppressive treatment for these conditions, with reduced side-effects compared to currently accepted therapies. Previously identified first-in-class inhibitors based on a 2-thioxoimidazolidin-4-one core show suboptimal physicochemical properties and toxicity toward the natural killer (NK) cells that secrete perforin in vivo. The current benzenesulphonamide-based series delivers a non-toxic bioisosteric replacement possessing improved solubility.