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Fragment-based and structure-guided discovery of perforin inhibitors.
Jose, Jiney; Law, Ruby H P; Leung, Eleanor W W; Wai, Dorothy C C; Akhlaghi, Hedieh; Chandrashekaran, Indu R; Caradoc-Davies, Tom T; Voskoboinik, Ilia; Feutrill, John; Middlemiss, David; Jeevarajah, Devadharshini; Bashtannyk-Puhalovich, Tanya; Giddens, Anna C; Lee, Tet Woo; Jamieson, Stephen M F; Trapani, Joseph A; Whisstock, James C; Spicer, Julie A; Norton, Raymond S.
Afiliación
  • Jose J; Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, A New Zealand Centre for Research Excellence, Auckland, New Zealand.
  • Law RHP; Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, 3800, Australia.
  • Leung EWW; Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia.
  • Wai DCC; Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia.
  • Akhlaghi H; Cancer Immunology Program, Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, VIC, 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, 3052, Australia.
  • Chandrashekaran IR; Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia; ARC Centre for Fragment-Based Design, Monash University, Parkville, VIC, 3052, Australia.
  • Caradoc-Davies TT; Australian Synchrotron, 800 Blackburn Rd., Clayton, Melbourne, VIC, 3168, Australia.
  • Voskoboinik I; Cancer Immunology Program, Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, VIC, 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, 3052, Australia.
  • Feutrill J; SYNthesis med chem (Australia) Pty Ltd, Bio21 Institute, 30 Flemington Road, Parkville, VIC, 3052, Australia.
  • Middlemiss D; XaviaPharm, Bishop's Stortford, CM23 5EX, England, United Kingdom.
  • Jeevarajah D; Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, 3800, Australia.
  • Bashtannyk-Puhalovich T; Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, 3800, Australia.
  • Giddens AC; Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand.
  • Lee TW; Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand.
  • Jamieson SMF; Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, A New Zealand Centre for Research Excellence, Auckland, New Zealand; Department of Pharmacol
  • Trapani JA; Cancer Immunology Program, Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, VIC, 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, 3052, Australia.
  • Whisstock JC; Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, 3800, Australia. Electronic address: James.Whisstock@monash.edu.
  • Spicer JA; Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, A New Zealand Centre for Research Excellence, Auckland, New Zealand. Electronic address: j.s
  • Norton RS; Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia; ARC Centre for Fragment-Based Design, Monash University, Parkville, VIC, 3052, Australia. Electronic address: ray.norton@monash.edu.
Eur J Med Chem ; 261: 115786, 2023 Dec 05.
Article en En | MEDLINE | ID: mdl-37716187
Perforin is a pore-forming protein whose normal function enables cytotoxic T and natural killer (NK) cells to kill virus-infected and transformed cells. Conversely, unwanted perforin activity can also result in auto-immune attack, graft rejection and aberrant responses to pathogens. Perforin is critical for the function of the granule exocytosis cell death pathway and is therefore a target for drug development. In this study, by screening a fragment library using NMR and surface plasmon resonance, we identified 4,4-diaminodiphenyl sulfone (dapsone) as a perforin ligand. We also found that dapsone has modest (mM) inhibitory activity of perforin lytic activity in a red blood cell lysis assay in vitro. Sequential modification of this lead fragment, guided by structural knowledge of the ligand binding site and binding pose, and supported by SPR and ligand-detected 19F NMR, enabled the design of nanomolar inhibitors of the cytolytic activity of intact NK cells against various tumour cell targets. Interestingly, the ligands we developed were largely inert with respect to direct perforin-mediated red blood cell lysis but were very potent in the context of perforin's action on delivering granzymes in the immune synapse, the context in which it functions physiologically. Our work indicates that a fragment-based, structure-guided drug discovery strategy can be used to identify novel ligands that bind perforin. Moreover, these molecules have superior physicochemical properties and solubility compared to previous generations of perforin ligands.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Células Asesinas Naturales / Dapsona Idioma: En Revista: Eur J Med Chem Año: 2023 Tipo del documento: Article País de afiliación: Nueva Zelanda Pais de publicación: Francia
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Células Asesinas Naturales / Dapsona Idioma: En Revista: Eur J Med Chem Año: 2023 Tipo del documento: Article País de afiliación: Nueva Zelanda Pais de publicación: Francia