Der Immuncheckpoint PD‐1/PD‐L1: Gibt es Therapieoptionen jenseits der Antikörper?

Konstantinidou, Markella; Zarganes‐Tzitzikas, Tryfon; Magiera‐Mularz, Katarzyna; Holak, Tad A.; Dömling, Alexander

doi:10.1002/ange.201710407

Cited by 4 publications

(1 citation statement)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, radiolabeled antibodies can present unfavorable characteristics such as low tissue penetration, costly production, slow pharmacokinetics and thus, longer diagnosis time (days to weeks). Smaller molecules with faster pharmacokinetics that are able to target protein‐protein interactions, in this case PD‐1/PD−L1, have recently gained attention in the field of radiopharmaceutical development [10] . In comparison to bulkier PD−L1 inhibitors (e. g., antibodies and other proteins), synthetically readily accessible peptides exhibit several advantages such as excellent specificity, low toxicity, good tissue penetration, fast pharmacokinetics, and low production costs.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of a Radiolabeled Macrocyclic Peptide as Potential PET Imaging Probe for PD−L1

2022

View full text Add to dashboard Cite

The interaction between the immune checkpoint PD-1 and PDÀ L1 promotes T-cell deactivation and cancer proliferation. Therefore, immune checkpoint inhibition therapy, which relies on prior assessment of the target, has been widely used for many cancers. As a non-invasive molecular imaging tool, radiotracers bring novel information on the in vivo expression of biomarkers (e. g., PDÀ L1), enabling a personalized treatment of patients. Our work aimed at the development of a PDÀ L1specific, peptide-based PET radiotracer. We synthesized and evaluated a radiolabeled macrocyclic peptide adapted from a patent by Bristol Myers Squibb. Synthesis of [ 68 Ga]Ga-NJMP1 yielded a product with a radiochemical purity > 95 % that was evaluated in vitro. However, experiments on CHOÀ K1 hPDÀ L1 cells showed very low cell binding and internalization rates of [ 68 Ga]Ga-NJMP1 in comparison to a control radiopeptide (WL12). Non-radioactive cellular assays using time-resolved fluorescence energy transfer confirmed the low affinity of the reported parent peptide and the DOTA-derivatives towards PDÀ L1. The results of our studies indicate that the macrocyclic peptide scaffold reported in the patent literature is not suitable for radiotracer development due to insufficient affinity towards PDÀ L1 and that C-terminal modifications of the macrocyclic peptide interfere with important ligand/receptor interactions.

show abstract

Section: Introductionmentioning

confidence: 99%

Evaluation of a Radiolabeled Macrocyclic Peptide as Potential PET Imaging Probe for PD−L1

2022

View full text Add to dashboard Cite

show abstract

Tailored Cross‐β Assemblies Establish Peptide “Dominos” Structures for Anchoring Undruggable Pharmacophores

Zhang

Wang

et al. 2022

Angewandte Chemie

View full text Add to dashboard Cite

β-sheets have the ability to hierarchically stack into assemblies, and much effort has been spent on designing different peptides to regulate their assembly behaviors. Although the progress is remarkable, it remains challenging to manipulate them in a controllable way for achieving both tailored structures and specific functions. In this study, we obtained bola-like peptides using de novo design and combinatorial chemical screening. By regulating the solvent-accessible surface area of the peptide chain, a series of assemblies with different tilt angles and active sites of the β-sheet were obtained, resembling collapsed dominos. The structure-activity relationship of the optimized peptide NQ40 system was established and its ability to target the PD-L1 was demonstrated. This study successfully established the structure-function relationship of β-sheets assemblies and has positive implications on the rational design of peptide assemblies that possess recognition abilities.

show abstract

Tailored Cross‐β Assemblies Establish Peptide “Dominos” Structures for Anchoring Undruggable Pharmacophores

Zhang

Wang

et al. 2022

Angew Chem Int Ed

View full text Add to dashboard Cite

β‐sheets have the ability to hierarchically stack into assemblies, and much effort has been spent on designing different peptides to regulate their assembly behaviors. Although the progress is remarkable, it remains challenging to manipulate them in a controllable way for achieving both tailored structures and specific functions. In this study, we obtained bola‐like peptides using de novo design and combinatorial chemical screening. By regulating the solvent‐accessible surface area of the peptide chain, a series of assemblies with different tilt angles and active sites of the β‐sheet were obtained, resembling collapsed dominos. The structure‐activity relationship of the optimized peptide NQ40 system was established and its ability to target the PD‐L1 was demonstrated. This study successfully established the structure‐function relationship of β‐sheets assemblies and has positive implications on the rational design of peptide assemblies that possess recognition abilities.

show abstract

Der Immuncheckpoint PD‐1/PD‐L1: Gibt es Therapieoptionen jenseits der Antikörper?

Cited by 4 publications

References 42 publications

Evaluation of a Radiolabeled Macrocyclic Peptide as Potential PET Imaging Probe for PD−L1

Evaluation of a Radiolabeled Macrocyclic Peptide as Potential PET Imaging Probe for PD−L1

Tailored Cross‐β Assemblies Establish Peptide “Dominos” Structures for Anchoring Undruggable Pharmacophores

Tailored Cross‐β Assemblies Establish Peptide “Dominos” Structures for Anchoring Undruggable Pharmacophores

Contact Info

Product

Resources

About