Benzenesulphonamide inhibitors of the cytolytic protein perforin

Julie A Spicer, Christian K. Miller, Patrick D. O'Connor, Jiney Jose, Kristiina M. Huttunen, Jagdish K. Jaiswal, William A Denny, Hedieh Akhlaghi, Kylie A Browne, Joseph A. Trapani

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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.

LanguageEnglish
Pages1050-1054
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume27
Issue number4
DOIs
Publication statusPublished - 15 Feb 2017
Externally publishedYes

Keywords

  • Benzenesulphonamide
  • Bioisostere
  • Immunosuppressant
  • Perforin
  • Perforin inhibitor

Cite this

Spicer, J. A., Miller, C. K., O'Connor, P. D., Jose, J., Huttunen, K. M., Jaiswal, J. K., ... Trapani, J. A. (2017). Benzenesulphonamide inhibitors of the cytolytic protein perforin. Bioorganic and Medicinal Chemistry Letters, 27(4), 1050-1054. https://doi.org/10.1016/j.bmcl.2016.12.057
Spicer, Julie A ; Miller, Christian K. ; O'Connor, Patrick D. ; Jose, Jiney ; Huttunen, Kristiina M. ; Jaiswal, Jagdish K. ; Denny, William A ; Akhlaghi, Hedieh ; Browne, Kylie A ; Trapani, Joseph A. / Benzenesulphonamide inhibitors of the cytolytic protein perforin. In: Bioorganic and Medicinal Chemistry Letters. 2017 ; Vol. 27, No. 4. pp. 1050-1054.
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Spicer, JA, Miller, CK, O'Connor, PD, Jose, J, Huttunen, KM, Jaiswal, JK, Denny, WA, Akhlaghi, H, Browne, KA & Trapani, JA 2017, 'Benzenesulphonamide inhibitors of the cytolytic protein perforin' Bioorganic and Medicinal Chemistry Letters, vol. 27, no. 4, pp. 1050-1054. https://doi.org/10.1016/j.bmcl.2016.12.057

Benzenesulphonamide inhibitors of the cytolytic protein perforin. / Spicer, Julie A; Miller, Christian K.; O'Connor, Patrick D.; Jose, Jiney; Huttunen, Kristiina M.; Jaiswal, Jagdish K.; Denny, William A; Akhlaghi, Hedieh; Browne, Kylie A; Trapani, Joseph A.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 27, No. 4, 15.02.2017, p. 1050-1054.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Jose, Jiney

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AU - Jaiswal, Jagdish K.

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Spicer JA, Miller CK, O'Connor PD, Jose J, Huttunen KM, Jaiswal JK et al. Benzenesulphonamide inhibitors of the cytolytic protein perforin. Bioorganic and Medicinal Chemistry Letters. 2017 Feb 15;27(4):1050-1054. https://doi.org/10.1016/j.bmcl.2016.12.057