Structure-based derivation and intramolecular cyclization of peptide inhibitors from PD-1/PD-L1 complex interface as immune checkpoint blockade for breast cancer immunotherapy.

Structure-based derivation and intramolecular cyclization of peptide inhibitors from PD-1/PD-L1 complex interface as immune checkpoint blockade for breast cancer immunotherapy. Biophys Chem. 2019 Jun 26;253:106213 Authors: Zhou K, Lu J, Yin X, Xu H, Li L, Ma B Abstract The interaction event between programmed death receptor-1 (PD-1) and its ligand (PD-L1) functions as an essential immune checkpoint against cytotoxic T effector cell activation. Previously, a number of small-molecule inhibitors and antibody drugs have been successfully developed to block the PD1/PDL1 signaling axis for breast cancer immunotherapy. Here, we attempt to directly disrupt the formation of PD-1/PD-L1 complex by using a self-inhibitory peptide (SIP) strategy. In the procedure, the complex crystal structure is examined systematically with energetic analysis and alanine scanning. Two double-stranded segments I and II in PD-L1 active finger are identified as hotspot regions; they directly interact with the amphipathic pocket of PD-1 to form the complex system. The segments are derived from PD-L1 to define two SIP peptides, namely, DS-I and DS-II, which are thought to have capability of rebinding at the complex interface, thus disrupting PD-1/PD-L1 interaction as a new immune checkpoint blockade. A further analysis reveals that the free linear DS-I and DS-II peptides are highly flexible without protein context support, which would incur a large entropy penalty (u...
Source: Biophysical Chemistry - Category: Chemistry Authors: Tags: Biophys Chem Source Type: research