%0 Journal Article
%T Study on endogenous inhibitors against PD-L1: cAMP as a potential candidate.
%A Huang Q
%A Zang X
%A Zhang Z
%A Yu H
%A Ding B
%A Li Z
%A Cheng S
%A Zhang X
%A Ali MRK
%A Qiu X
%A Lv Z
%J Int J Biol Macromol
%V 230
%N 0
%D Mar 2023 1
%M 36646351
%F 8.025
%R 10.1016/j.ijbiomac.2023.123266
%X The discovery of new anti-cancer drugs targeting the PD-1/PD-L1 pathway has been a research hotspot in recent years. In this study, biological affinity ultrafiltration (BAU), UPLC-HRMS, molecular dynamic (MD) simulations and molecular docking methods were applied to search for endogenous active compounds that can inhibit the binding of PD-L1 to PD-1. We screened dozens of potential cancer related endogenous compounds. Surprisingly, cyclic adenosine monophosphate (cAMP) was found to have a direct inhibitory effect on the PD-1/PD-L1 binding with an in vitro IC50 value of about 36.4 ± 9.3 μM determined by homogeneous time-resolved fluorescence (HTRF) assay. cAMP could recover the proliferation of Jurkat T cells co-cultured with DU-145 cells and may suppress PD-L1 expression of DU-145 cells. cAMP was demonstrated to bind and induce PD-L1 dimerization by FRET assay, and also predicted by MD simulations and molecular docking. The finding of cAMP as a potential inhibitor directly targeting the PD-1/PD-L1 interaction could advance our understanding of the activity of endogenous compounds regulating PD-L1.