Inhibition of the Cytolytic Protein Perforin Prevents Rejection of Transplanted Bone Marrow Stem Cells in Vivo
| Autor: | William A. Denny, Stephen M. F. Jamieson, Christian K. Miller, Kate H. Gartlan, Julie Ann Spicer, Jiney Jose, Karshing Chang, Matthew Bull, Hedieh Akhlaghi, Joseph A. Trapani, Jagdish K. Jaiswal, Geoff R. Hill, Patrick D. O'Connor, Anna C. Giddens |
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| Rok vydání: | 2019 |
| Předmět: |
Graft Rejection
Male chemical and pharmacologic phenomena Context (language use) 01 natural sciences Cell Line Bone Marrow Stem Cell Transplantation Mice 03 medical and health sciences In vivo Drug Discovery Animals Cytotoxic T cell Bone Marrow Transplantation 030304 developmental biology Mice Inbred BALB C Sulfonamides 0303 health sciences biology Perforin Chemistry 3. Good health 0104 chemical sciences Mice Inbred C57BL 010404 medicinal & biomolecular chemistry Granzyme Cell culture biology.protein Cancer research Molecular Medicine Stem cell Stem Cell Transplantation |
| Zdroj: | Journal of Medicinal Chemistry. 63:2229-2239 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.9b00881 |
| Popis: | Perforin is a key effector protein in the vertebrate immune system and is secreted by cytotoxic T lymphocytes and natural killer cells to help eliminate virus-infected and transformed target cells. The ability to modulate perforin activity in vivo could be extremely useful, especially in the context of bone marrow stem cell transplantation where early rejection of immunologically mismatched grafts is driven by the recipient's natural killer cells, which overwhelmingly use perforin to kill their targets. Bone marrow stem cell transplantation is a potentially curative treatment for both malignant and nonmalignant disorders, but when the body recognizes the graft as foreign, it is rejected by this process, often with fatal consequences. Here we report optimization of a previously identified series of benzenesulfonamide-based perforin inhibitors for their physicochemical and pharmacokinetic properties, resulting in the identification of 16, the first reported small molecule able to prevent rejection of transplanted bone marrow stem cells in vivo by blocking perforin function. |
| Databáze: | OpenAIRE |
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