RapaLink-1 outperforms rapamycin in alleviating allogeneic graft rejection by inhibiting the mTORC1-4E-BP1 pathway in mice.

[Display omitted] • RapaLink-1 exhibits more pronounced inhibition of T lymphocyte proliferation compared to rapamycin. • RapaLink-1 is more effective in improving murine allograft rejection and has an acceptable safety profile within a certain dosage range. • RapaLink-1 suppresses immune activation, promotes Treg cells, and reduces inflammatory Th1 and Th17 cells to inhibit rejection reactions. • The inhibitory effect of RapaLink-1 on T cell proliferation in vitro and in vivo is associated with its negative regulation of the T lymphocyte mTORC1-4E-BP1 pathway. Inhibition of mammalian target of rapamycin (mTOR), which is a component of both mTORC1 and mTORC2, leads to clinical benefits for organ transplant recipients. Pathways to inhibit mTOR include strengthening the association of FKBP12-mTOR or competing with ATP at the active site of mTOR, which have been applied to the design of first- and second-generation mTOR inhibitors, respectively. However, the clinical efficacy of these mTOR inhibitors may be limited by side effects, compensatory activation of kinases and attenuation of feedback inhibition of receptor expression. A new generation of mTOR inhibitors possess a core structure similar to rapamycin and covalently link to mTOR kinase inhibitors, resulting in moderate selectivity and potent inhibition of mTORC1. Since the immunosuppressive potential of this class of compounds remains unknown, our goal is to examine the therapeutic efficacy of a third-generation mTOR inhibitor in organ transplantation. In this study, RapaLink-1 outperformed rapamycin in inhibiting T-cell proliferation and significantly prolonged graft survival time. Mechanistically, the ameliorated rejection induced by RapaLink-1 is associated with a reduction in p-4E-BP1 in T cells, resulting in an elevation in Treg cells alongside a decline in Th1 and Th17 cells. For the first time, these studies demonstrate the effectiveness of third-generation mTOR inhibitors in inhibiting allograft rejection, highlighting the potential of this novel class of mTOR inhibitors for further investigation. [ABSTRACT FROM AUTHOR]