Back to Search
Start Over
Structural Characterization of a Macrocyclic Peptide Modulator of the PD-1/PD-L1 Immune Checkpoint Axis.
- Source :
-
Molecules (Basel, Switzerland) [Molecules] 2021 Aug 11; Vol. 26 (16). Date of Electronic Publication: 2021 Aug 11. - Publication Year :
- 2021
-
Abstract
- The clinical success of PD-1/PD-L1 immune checkpoint targeting antibodies in cancer is followed by efforts to develop small molecule inhibitors with better penetration into solid tumors and more favorable pharmacokinetics. Here we report the crystal structure of a macrocyclic peptide inhibitor (peptide 104) in complex with PD-L1. Our structure shows no indication of an unusual bifurcated binding mode demonstrated earlier for another peptide of the same family (peptide 101). The binding mode relies on extensive hydrophobic interactions at the center of the binding surface and an electrostatic patch at the side. An interesting sulfur/π interaction supports the macrocycle-receptor binding. Overall, our results allow a better understanding of forces guiding macrocycle affinity for PD-L1, providing a rationale for future structure-based inhibitor design and rational optimization.
- Subjects :
- Animals
CHO Cells
Cricetulus
Humans
Jurkat Cells
Magnetic Resonance Spectroscopy
Models, Molecular
Protein Binding
B7-H1 Antigen metabolism
Immune Checkpoint Proteins metabolism
Macrocyclic Compounds chemistry
Macrocyclic Compounds pharmacology
Peptides chemistry
Peptides pharmacology
Programmed Cell Death 1 Receptor metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1420-3049
- Volume :
- 26
- Issue :
- 16
- Database :
- MEDLINE
- Journal :
- Molecules (Basel, Switzerland)
- Publication Type :
- Academic Journal
- Accession number :
- 34443436
- Full Text :
- https://doi.org/10.3390/molecules26164848