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SERS nanostructures with engineered active peptides against an immune checkpoint protein
Marina Gobbo1, Isabella Caligiuri2, Micaela Giannetti3
1Department of Chemical Sciences, University of Padova, via F. Marzolo 1, 35131 Padova, Italy. moreno.meneghetti@unipd.it.
Abstract:
The immune checkpoint programmed death ligand 1 (PD-L1) protein is expressed by tumor cells and it suppresses the killer activity of CD8+ T-lymphocyte cells binding to the programmed death 1 (PD-1) protein of these immune cells. Binding to either PD-L1 or PD1 is used for avoiding the inactivation of CD8+ T-lymphocyte cells. We report, for the first time, Au plasmonic nanostructures with surface-enhanced Raman scattering (SERS) properties (SERS nanostructures) and functionalized with an engineered peptide (CLP002: Trp-His-Arg-Ser-Tyr-Tyr-Thr-Trp-Asn-Leu-Asn-Thr), which targets PD-L1. Molecular dynamics calculations are used to describe the interaction of the targeting peptide with PD-L1 in the region where the interaction with PD-1 occurs, showing also the poor targeting activity of a peptide with the same amino acids, but a scrambled sequence. The results are confirmed experimentally since a very good targeting activity is observed against the MDA-MB-231 breast adenocarcinoma cancer cell line, which overexpresses PD-L1. A good activity is observed, in particular, for SERS nanostructures where the CLP002-engineered peptide is linked to the nanostructure surface with a short charged amino acid sequence and a long PEG chain. The results show that the functionalized SERS nanostructures show very good targeting of the immune checkpoint PD-L1.
Insights
Researchers developed novel gold nanostructures functionalized with a peptide (CLP002) that effectively targets the programmed death ligand 1 (PD-L1) immune checkpoint. This advancement shows promise for cancer therapies by enhancing T-cell activity against tumors.
Area of Science:
- Biotechnology and Nanomedicine
- Immunology and Cancer Research
Background:
- The programmed death ligand 1 (PD-L1) protein on tumor cells inhibits CD8+ T-lymphocyte activity by binding to PD-1.
- Targeting the PD-L1/PD-1 interaction is a key strategy in cancer immunotherapy to restore anti-tumor immune responses.
Purpose of the Study:
- To engineer and evaluate gold plasmonic nanostructures functionalized with a peptide (CLP002) for targeting PD-L1.
- To investigate the targeting efficacy of these nanostructures against cancer cells overexpressing PD-L1.
Main Methods:
- Design and synthesis of gold plasmonic nanostructures with surface-enhanced Raman scattering (SERS) properties.
- Functionalization of nanostructures with an engineered peptide (CLP002) targeting PD-L1.
- Molecular dynamics simulations to predict peptide-PD-L1 interactions and experimental validation using MDA-MB-231 cancer cells.
Main Results:
- Molecular dynamics simulations confirmed the specific targeting interaction of CLP002 with PD-L1.
- Experimentally, the functionalized SERS nanostructures demonstrated significant targeting activity against PD-L1-overexpressing MDA-MB-231 breast cancer cells.
- Optimal targeting was observed when CLP002 was linked to the nanostructure surface via a short charged sequence and a long PEG chain.
Conclusions:
- The study successfully developed PD-L1-targeting SERS nanostructures functionalized with the engineered peptide CLP002.
- These functionalized nanostructures represent a promising tool for targeted cancer immunotherapy by modulating the PD-L1 immune checkpoint.
