Peptide-based cancer therapies can be used to selectively target tumors for drug delivery by targeting receptors overexpressed on tumor cells, thereby reducing toxicity to healthy cells. In particular, low-density lipoprotein receptor-related protein 1 (LRP1) is overexpressed on glioblastoma cell surfaces and brain capillary endothelial cells, and the synthetic peptide angiopep-2 derived from aprotinin has been shown to have blood brain barrier permeability and selectively bind to LRP1 with high affinity. In this work, we utilized a computational approach to develop novel peptide mutants of angiopep-2 as well as peptide-neurotransmitter conjugates with higher predicted binding affinities to LRP1 than the original angiopep-2 ligand for potential use as targeted therapies for the treatment of human glioblastoma. The AntiCP Webserver was used to predict the anticancer properties of several point mutations of angiopep-2, and the mutations with the highest predicted anticancer properties and their neurotransmitter conjugates were docked to the barrel domain of the LRP1 receptor using a multitude of docking techniques to validate our study. This domain of the LRP1 receptor is known to facilitate the receptor-mediated transcytosis of angiopep-2 through the blood brain barrier, and the structure was predicted using the ITASSER webserver. The best ligand-receptor docking candidates were examined through atomistic molecular dynamics simulations to examine the stability and binding mechanism of each receptor-ligand complex, and MM-GBSA calculations were used to estimate ligand binding affinities. Several mutated sequences, as well as peptide-serotonin conjugates, were demonstrated to show increased binding affinity to the barrel domain of LRP1 compared to the original angiopep-2 peptide, demonstrating the potential to be used in drug delivery systems for the treatment of human glioblastoma.

Computational approach to developing anticancer peptide-neurotransmitter conjugates for targeted drug delivery to human glioblastoma tumors via the LRP1 receptor

ACS Spring 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.