Cycling Molecular Assemblies for Selective Cancer Cell Golgi Disruption.

Area of Science:

• Cell Biology
• Biochemistry
• Drug Discovery

Background:

• The Golgi apparatus is vital for intracellular trafficking and signaling, with its dysfunction linked to diseases like cancer.
• Targeting the Golgi apparatus presents a therapeutic opportunity, but selective cell targeting remains a challenge.
• Existing methods lack cell selectivity, necessitating innovative strategies for Golgi-specific disruption in cancer.

Purpose of the Study:

• To develop novel small peptide derivatives, cycling molecular assemblies (CyMA), for selective Golgi apparatus targeting in cancer cells.
• To exploit the Golgi's unique enzymatic environment for targeted therapeutic intervention.
• To investigate CyMA's potential in disrupting cancer cell function and progression.

Main Methods:

• Development of cycling molecular assemblies (CyMA) based on small peptide derivatives.
• Exploitation of Golgi-specific enzyme activities (e.g., protein acyltransferases) to establish futile cycles of S-acylation.
• Assessment of CyMA's selective accumulation in cancer cell Golgi and impact on organelle homeostasis.

Main Results:

• CyMA selectively accumulate in cancer cell Golgi, disrupting protein S-acylation and organelle homeostasis.
• CyMA impair key Golgi functions including protein trafficking, glycosylation, and secretion.
• CyMA demonstrated selective sparing of hepatocytes and M1 macrophages, reducing tumor growth, drug resistance, and metastasis.

Conclusions:

• Cycling molecular assemblies (CyMA) represent a novel therapeutic strategy by leveraging organelle-specific enzyme activities.
• This approach offers a generalizable method for targeting specific organelle functions, particularly in cancer.
• CyMA show significant therapeutic potential for cancer and other Golgi-associated diseases.