Discovery, X-ray structure and CPP-conjugation enabled uptake of p53/MDM2 macrocyclic peptide inhibitors.
Anselm F L SchneiderJoerg KallenJohannes OttlPatrick C ReidSebastien RipocheStephan RuetzTherese-Marie StachyraSamuel HintermannChristoph E DumelinChristian P R HackenbergerAndreas L MarzinzikPublished in: RSC chemical biology (2021)
Mouse double minute 2 homolog (MDM2, Hdm2) is an important negative regulator of the tumor suppressor p53. Using a mRNA based display technique to screen a library of >10 12 in vitro -translated cyclic peptides, we have identified a macrocyclic ligand that shows picomolar potency on MDM2. X-Ray crystallography reveals a novel binding mode utilizing a unique pharmacophore to occupy the Phe/Trp/Leu pockets on MDM2. Conjugation of a cyclic cell-penetrating peptide (cCPP) to the initially non cell-permeable ligand enables cellular uptake and a pharmacodynamic response in SJSA-1 cells. The demonstrated enhanced intracellular availability of cyclic peptides that are identified by a display technology exemplifies a process for the application of intracellular tools for drug discovery projects.
Keyphrases
- drug discovery
- single cell
- high resolution
- high throughput
- cell therapy
- induced apoptosis
- small molecule
- reactive oxygen species
- stem cells
- cell cycle arrest
- binding protein
- molecular dynamics
- molecular docking
- transcription factor
- amino acid
- computed tomography
- magnetic resonance
- bone marrow
- oxidative stress
- electron microscopy
- mass spectrometry
- cell proliferation
- endoplasmic reticulum stress
- molecular dynamics simulations