Spatial orientation of ligands for improved biological functions

Researchers discovered that the spatial orientation of ligands plays a more critical role than mere incorporation. They validated their hypothesis by conjugating the amino acid histidine through a five-armed ring oligomer into a cationic polymer. This work was published in the journal Biofunctional Materials in December 2024. Alongside their other published studies, they reaffirmed that the spatial orientation is a crucial parameter for optimizing cellular functions mediated by ligand-receptor interactions.

Ligand-receptor interactions play a key role in many biological functions, including cell metabolism and development, cell signaling, immune response, and tissue homeostasis. Consequently, these interactions have been widely studied in various biomedical research applications, such as drug development and biosensors. The critical factors influencing ligand-receptor interactions include ligand density, linker chain length, and the spatial orientation of the ligand. In their manuscript entitled “The Spatial Orientation of Histidine via Five-Armed Alkylamino Siloxane Improved the Properties of the Cationic Gene Delivery Vector”, Dr. Morris and Dr. Sharma demonstrated how the spatial orientation of the ligand histidine, conjugated to the core cationic polymer polyethylenimine via a five-armed alkylamino siloxane linker group, enhances gene transfection efficiency.

Due to steric effects, overcrowding of ligands may hinder their interactions with cell surface receptors, nullifying their biological outcomes,” says Dr. Morris, who began this project as a graduate student at Sree Chitra Tirunal Institute, India, under the guidance of Dr. Sharma. Dr. Morris is now a Research Scientist at Emory University School of Medicine in the USA. “In addition to optimal ligand density, the linker group between the core polymer and the ligand also influences ligand-receptor interactions. The 3D orientation of the ligand toward the cell surface receptor depends on the linker’s chain length and flexibility,” she adds.

They varied the ligand density around the cationic core polymer in ratios such as 1:1, 1:5, 1:10, and 1:15, while keeping the equivalents of the cationic polymer constant. However, due to steric effects, no improvement in gene expression was observed with an increase in ligand density. Instead, the highest gene expression and lowest toxicity were achieved at a ligand density of 1:1. “This indicates that it is not the ligand density but the spatial orientation of the ligand, facilitated by flexible linker groups, that enhances biological properties through optimal ligand-receptor interactions,” comments Dr. Sharma.

Morris VB, Sharma CP. The spatial orientation of histidine via five-armed alkylamino siloxane improved the properties of the cationic gene delivery vector. Biofunct. Mater. 2024(2):0010, https://doi.org/10.55092/bm20240010.