Stapled Peptides That Target Cancer Protein NONO Unexpectedly Enter Cells and Reach the Nucleus | Research

The takeaway

Researchers designed stapled peptides targeting the cancer-linked protein NONO and discovered they naturally penetrate cells and localize to the nucleus — two properties that are extremely difficult to engineer.

Cell + nuclear entry
Stapled peptides achieved both cell permeability and nuclear localization — properties rarely seen together in designed peptides

What the researchers found

Stapled peptides derived from IGFBP-3 and NONO dimerization sequences demonstrated unexpected cell permeability and preferential nuclear localization, despite only modest binding affinity to the NONO dimer.

Why it matters

Cell permeability and nuclear targeting are two of the biggest hurdles in peptide drug development. Finding peptides that achieve both naturally opens a new path for designing drugs against nuclear cancer targets like NONO.

The numbers in context

Stapled peptides achieved both cell penetration and nuclear localization — properties rarely seen together in designed peptides.

How the study worked

In vitro study using multiple peptide stapling chemistries (Pd-catalyzed cross-coupling, cysteine arylation, cysteine alkylation) to create macrocyclic helical peptides. Cell permeability and nuclear localization assessed via live confocal microscopy with dye-labeled peptides.

Who was studied

Cell culture studies with designed stapled peptides

What this study cannot tell us

NONO binding was modest and could not be saturated. No functional anticancer activity demonstrated. Only tested in cell culture — no animal or clinical data. Nuclear localization mechanism not fully understood.

How to read the evidence

Preliminary evidence: early-stage in vitro work demonstrating proof-of-concept for cell permeability and nuclear targeting, but no functional activity or in vivo data yet.

When this study was published

Published in 2024. Represents current state of stapled peptide technology.

The bigger picture

Most peptide drugs cannot enter cells, let alone reach the nucleus. This unexpected finding could accelerate the development of peptide-based cancer therapies targeting intracellular proteins, an area where traditional drug design has struggled.

Questions still open

What structural features of these stapled peptides enable their unexpected cell permeability and nuclear entry?
Can binding affinity to NONO be improved through further peptide optimization?
Will these peptides show anticancer activity in NONO-dependent cancer models?

Common questions

What are stapled peptides and why do they matter?

Stapled peptides are small protein fragments chemically reinforced with a molecular "staple" that locks them into a specific shape. This makes them more stable, more resistant to degradation, and sometimes better at entering cells than regular peptides.

Could this lead to a new cancer treatment?

It is very early, but the ability to get peptides into the nucleus is a major breakthrough step. If researchers can improve binding to the NONO cancer target, these peptides could become the basis for new cancer therapies.

Read the original research

Development of stapled NONO-associated peptides reveals unexpected cell permeability and nuclear localisation.

Journal of peptide science : an official publication of the European Peptide Society, 30(5), e3562

View on PubMed ↗Publisher’s paper ↗

Citation

Young, Reginald; Huang, Tiancheng; Luo, Zijie; Tan, Yaw Sing; Kaur, Amandeep; Lau, Yu Heng. (2024). Development of stapled NONO-associated peptides reveals unexpected cell permeability and nuclear localisation.. Journal of peptide science : an official publication of the European Peptide Society, 30(5), e3562. https://doi.org/10.1002/psc.3562