Structural Features of the Extracellular Region of Programmed Cell Death Ligand-1 and the Implications for Therapeutic Targeting
thesisposted on 01.08.2019, 09:30 by Kayleigh L. Walker
The use of antibody immune checkpoint inhibitors of the PD-1/PD-L1 interaction has recently emerged as a great success in the treatment of cancer. The development of small-molecule inhibitors targeting the PD-1/PDL1 interaction lags behind. There are however, a series of bi-phenyl derived compounds patented by Bristol-Myers Squibb, that have been shown to block the PD-1/PD-L1 interaction in vitro but have no cellular activity. The work reported here uses NMR chemical shift perturbation analysis to characterise the binding of one of these small-molecules to PD-L1. Currently the only published structural information regarding these molecules binding to PD-L1 focuses on only the IgV-like domain of PD-L1. The work reported here shows that the BMS compound appears to bind to the full extracellular region of PD-L1 with a much-reduced affinity than what has been reported for the single IgV-like domain, shedding light on why these compounds have not been shown to have cellular activity and suggesting that development of small-molecules targeting PD-L1 should be performed with the full extracellular region of PD-L1. Backbone resonance assignment of the full extracellular region of PD-L1 and the two Ig-like domains in isolation has allowed the identification of an interface between the domains of PD-L1. Chemical shift perturbation analysis suggests that this interface may be augmented when PD-L1 binds to PD-1. Since PD-L1 has been shown to bind to binding partners on the same membrane, as well as across cell membranes, we propose that an interface between the domains of the extracellular region of PD-L1 is a mechanism through which PD-L1 can switch the orientation of the IgV-like domain depending on whether it is binding to a partner on the same membrane or across membranes. This could have important implications for the design of therapeutics that seek to modulate the binding of PD-L1 to its binding partners.