Related Experiment Video

Updated: Dec 19, 2025

Subcellular Fractionation for ERK Activation Upon Mitochondrial-derived Peptide Treatment
07:55

Subcellular Fractionation for ERK Activation Upon Mitochondrial-derived Peptide Treatment

Published on: September 25, 2017

8.2K

Cytosolic delivery of peptidic STAT3 SH2 domain inhibitors

Robert A Cerulli1, Livia Shehaj2, Isidora Tosic3

  • 1Cell, Molecular and Developmental Biology Program, Graduate School of Biomedical Sciences, Tufts University, Boston, MA 02111, United States.

Bioorganic & Medicinal Chemistry
|June 7, 2020
PubMed

Insights

Researchers developed peptide inhibitors targeting the STAT3 protein, crucial in cancer. While achieving cell delivery and stability, these peptides failed to inhibit STAT3 activity, highlighting challenges in designing effective cancer therapeutics.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Signal transducer and activator of transcription 3 (STAT3) is constitutively active in numerous cancers.
  • Inhibiting the STAT3 Src Homology 2 (SH2) domain is a potential therapeutic strategy.
  • Existing phosphotyrosine mimics used for inhibition have poor bioavailability.

Purpose of the Study:

  • To develop peptide-based inhibitors targeting the STAT3-SH2 domain.
  • To combine STAT3-specific sequences, stable phosphotyrosine isosteres, and cell-penetrating peptides.
  • To investigate the factors influencing the biological activity of these peptide inhibitors.

Main Methods:

  • Design and synthesis of peptide inhibitors incorporating STAT3-specific sequences and non-hydrolyzable phosphotyrosine isosteres.
  • Utilizing a high-efficiency cell-penetrating peptide for cytosolic delivery.
  • Quantitative cell-based assays to assess biological stability and delivery.
  • In vitro evaluation of binding affinity, cell penetration, and proteolytic stability.

Main Results:

  • Peptides demonstrated significant biological stability and successful cytosolic delivery in cell-based assays.
  • Despite stability and delivery, the designed peptides did not inhibit STAT3 activity in cellular models.
  • Comparative analysis revealed a complex interplay between binding affinity, cell penetration, and stability.

Conclusions:

  • Achieving effective inhibition of STAT3-SH2 in cells requires more than just stability and delivery.
  • The balance between in vitro properties and in vivo efficacy is critical for peptidic inhibitor design.
  • Further research is needed to optimize peptide structures for potent STAT3 inhibition in cancer therapy.
Keywords:
Cell-penetrating peptideChloroalkane penetration assayPhosphonatesSH2 domainSTAT3Transcription factor

More Related Videos

Biotinylated Cell-penetrating Peptides to Study Intracellular Protein-protein Interactions10:26

Biotinylated Cell-penetrating Peptides to Study Intracellular Protein-protein Interactions

Published on: December 20, 2017

9.8K
Delivery of Proteins, Peptides or Cell-impermeable Small Molecules into Live Cells by Incubation with the Endosomolytic Reagent dfTAT10:30

Delivery of Proteins, Peptides or Cell-impermeable Small Molecules into Live Cells by Incubation with the Endosomolytic Reagent dfTAT

Published on: September 2, 2015

10.6K

Related Concept Videos

The JAK-STAT Signaling Pathway01:20

The JAK-STAT Signaling Pathway

Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as  SH2...
11.4K
PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a...
5.1K
Translocation of Proteins into the Mitochondria01:19

Translocation of Proteins into the Mitochondria

Mitochondrial precursors are translocated to the internal subcompartments via independent mechanisms involving distinct protein machineries called translocases.
Sorting of outer membrane proteins:
Mitochondrial outer membrane proteins are of two types: the transmembrane, beta-barrel porins, and the membrane-anchored, alpha-helical proteins. Beta-barrel porin precursors are translocated by the TOM complex and inserted into the outer mitochondrial membrane by the SAM complex. In contrast,...
11.6K
Assembly of Signaling Complexes01:30

Assembly of Signaling Complexes

Multiprotein signaling complexes are formed in a dynamic process involving protein-protein interactions at the cytoplasmic domain of transmembrane receptors or enzymatic and non-enzymatic proteins associated with the receptor. These complexes ensure the activation and propagation of intracellular signals that regulate cell functions.
Interaction domains in cell signaling
Interaction domains recognize exposed features of their binding partners containing post-translationally modified sequences,...
6.4K
Amplifying Signals via Enzymatic Cascade01:22

Amplifying Signals via Enzymatic Cascade

When a ligand binds to a cell-surface receptor, the receptor's intracellular domain changes shape, which may either activate its enzyme function or allow its binding to other molecules. The initial signal is amplified by most signal transduction pathways. This means that a single ligand molecule can activate multiple molecules of a downstream target. Proteins that relay a signal are most commonly phosphorylated at one or more sites, activating or inactivating the protein. Kinases catalyze...
16.7K
Phosphoinositides and PIPs01:42

Phosphoinositides and PIPs

Phosphoinositides are a group of phospholipids containing a glycerol backbone with two fatty acid chains and a phosphate attached to a myoinositol sugar ring. The inositol head group extends into the cytoplasm, where it is modified by adding phosphate groups to form phosphatidylinositol phosphates or PIPs.
Different phosphoinositides are synthesized and recruited on the cytosolic face of the plasma membrane. The localization of specific phosphoinositides concentrated in separate membrane...
9.9K