Related Experiment Video

Updated: Aug 3, 2025

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors
10:33

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors

Published on: October 26, 2015

11.4K

A Cdk5-derived peptide inhibits Cdk5/p25 activity and improves neurodegenerative phenotypes

Ping-Chieh Pao1,2, Jinsoo Seo1,2,3, Audrey Lee1,2

  • 1Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139.

Proceedings of the National Academy of Sciences of the United States of America
|April 12, 2023
PubMed

Insights

A novel peptide inhibitor, Cdk5i, effectively targets the Cdk5/p25 complex implicated in neurodegeneration. This brain-penetrant peptide shows therapeutic potential for treating neurodegenerative diseases by reducing aberrant kinase activity.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Biochemistry

Background:

  • Aberrant cyclin-dependent kinase 5 (Cdk5) activity is linked to neurodegenerative diseases.
  • Pathological cleavage of the Cdk5 activator p35 to p25 prolongs kinase activation and alters substrate specificity, contributing to neurodegeneration.

Purpose of the Study:

  • To develop a novel, small peptide inhibitor targeting the Cdk5/p25 complex.
  • To evaluate the therapeutic potential of this peptide in cellular and animal models of neurodegeneration.

Main Methods:

  • Design and synthesis of a 12-amino-acid peptide fragment (Cdk5i) derived from Cdk5.
  • Assessment of Cdk5i binding affinity to the Cdk5/p25 complex and its inhibitory activity.
  • Conjugation of Cdk5i with a fluorophore (FITC) and cell-penetrating sequence (TAT) to create Cdk5i-FT.
  • Evaluation of Cdk5i-FT's cell and brain penetration and its protective effects in neurodegeneration models.

Main Results:

  • Cdk5i demonstrated high binding affinity for the Cdk5/p25 complex, disrupting their interaction and reducing kinase activity.
  • The Cdk5i-FT peptide exhibited cell- and brain-penetrant properties.
  • Cdk5i-FT conferred protection against neurodegenerative phenotypes in cell and mouse models.

Conclusions:

  • The novel peptide Cdk5i effectively inhibits the Cdk5/p25 complex.
  • Cdk5i-FT shows promise as a therapeutic agent for neurodegenerative diseases due to its brain penetrance and protective effects.
Keywords:
Alzheimer’s diseaseCdk5neurodegenerative diseasetauopathy

More Related Videos

Rapid Detection of Neurodevelopmental Phenotypes in Human Neural Precursor Cells NPCs10:47

Rapid Detection of Neurodevelopmental Phenotypes in Human Neural Precursor Cells NPCs

Published on: March 2, 2018

10.1K
Measuring RAN Peptide Toxicity in C. elegans10:49

Measuring RAN Peptide Toxicity in C. elegans

Published on: April 30, 2020

6.7K

Related Concept Videos

Inhibition of Cdk Activity02:34

Inhibition of Cdk Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
4.8K
Anaphase Promoting Complex00:50

Anaphase Promoting Complex

The stepwise destruction of specific proteins is necessary for the progression and completion of the cell cycle. Such proteins are ubiquitinated by ubiquitin ligases and then subsequently destroyed by the proteasome. The SCF (Skp1/Cullin/F-box) and the anaphase-promoting complex (APC) are two important ubiquitin ligases involved in cell cycle progression. While SCF is active throughout the cell cycle, APC gets activated during metaphase to anaphase transition. Cdc20 or Cdh1 binds to APC and...
2.9K
Positive Regulator Molecules02:39

Positive Regulator Molecules

Mitotic cell division results in daughter cells that exactly resemble the parent cell. However, errors in the DNA replication or distribution of genetic material may lead to genetic mutations that may be passed down to every new cell formed from the resulting abnormal cell. Propagation of such mutant cells is restricted through checkpoint mechanisms present at different stages of the cell cycle. These checkpoints involve regulator molecules that either promote or demote cell cycle events.
5.5K
M-Cdk Drives Transition Into Mitosis02:15

M-Cdk Drives Transition Into Mitosis

Checkpoints throughout the cell cycle serve as safeguards and gatekeepers, allowing the cell cycle to progress in favorable conditions and slow or halt it in problematic ones. This regulation is known as the cell cycle control system.
Cyclin-dependent kinases, or Cdks, work in concert with cyclins to control cell cycle transitions. M-Cdk, a complex of Cdk1 bound to M cyclin, is a well-known example of this coordinated control that drives the transition from the G2 to the M phase.
M cyclin...
5.6K
Abnormal Proliferation02:23

Abnormal Proliferation

Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
4.6K
Negative Regulator Molecules01:23

Negative Regulator Molecules

Positive regulators allow a cell to advance through cell cycle checkpoints. Negative regulators have an equally important role as they terminate a cell’s progression through the cell cycle—or pause it—until the cell meets specific criteria.
35.5K