Novel Cell-Penetrating Peptide Conjugated Proteasome Inhibitors: Anticancer and Antifungal Investigations

Kamal D Patel; Gayan Heruka De Zoysa; Manju Kanamala; Krunal Patel; Lisa I Pilkington; David Barker; Jóhannes Reynisson; Zimei Wu; Vijayalekshmi Sarojini

doi:10.1021/acs.jmedchem.9b01694

Novel Cell-Penetrating Peptide Conjugated Proteasome Inhibitors: Anticancer and Antifungal Investigations

J Med Chem. 2020 Jan 9;63(1):334-348. doi: 10.1021/acs.jmedchem.9b01694. Epub 2019 Dec 31.

Authors

Kamal D Patel¹, Gayan Heruka De Zoysa¹, Manju Kanamala², Krunal Patel¹, Lisa I Pilkington¹, David Barker¹, Jóhannes Reynisson³, Zimei Wu², Vijayalekshmi Sarojini^{1

4}

Affiliations

¹ School of Chemical Sciences and the Centre for Green Chemical Science , University of Auckland , Auckland 1142 , New Zealand.
² School of Pharmacy , University of Auckland , Auckland 1142 , New Zealand.
³ School of Pharmacy and Bioengineering, Hornbeam Building, Keele University , Staffordshire ST5 5BG , United Kingdom.
⁴ The MacDiarmid Institute for Advanced Materials and Nanotechnology , Wellington 6140 , New Zealand.

PMID: 31801019
DOI: 10.1021/acs.jmedchem.9b01694

Abstract

Cell-penetrating peptide conjugated peptide aldehydes Tat-A and Tat-B showed low micromolar anticancer and antifungal activities and synergistic action in combination with cisplatin and amphotericin B against cancer and fungal cells, respectively. Tat-A and Tat-B were significantly more potent than Ixazomib in inhibiting the human 20S proteasomes with IC₅₀ values in the low nanomolar range. Treatment with Tat-A and Tat-B caused membrane disruption and pore formation in HeLa and BE(2)-C cells and inhibition and eradication of C. albicans biofilms. Apoptotic cell death of the treated HeLa and BE(2)-C cells was demonstrated by Annexin V/PI staining. Flow cytometry analyses showed that more than 78% (HeLa) and 92% (BE(2)-C cells showed signs of apoptosis and necrosis upon treatment with Tat-A and Tat-B. This study forms the first report that documents the benefits of cell-penetrating peptide conjugation to enhance the potential of peptide aldehydes as therapeutics.

MeSH terms

Aldehydes / chemical synthesis
Aldehydes / pharmacology*
Amphotericin B / pharmacology
Animals
Antifungal Agents / chemical synthesis
Antifungal Agents / pharmacology*
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Biofilms / drug effects
Candida albicans / drug effects
Candida albicans / physiology
Cell Line, Tumor
Cell Membrane / drug effects
Cell-Penetrating Peptides / chemical synthesis
Cell-Penetrating Peptides / pharmacology*
Cisplatin / pharmacology
DNA / drug effects
Drug Synergism
Hemolysis / drug effects
Humans
Mice
Microbial Sensitivity Tests
Molecular Docking Simulation
Proteasome Endopeptidase Complex / metabolism
Proteasome Inhibitors / chemical synthesis
Proteasome Inhibitors / pharmacology*
Reactive Oxygen Species / metabolism

Substances

Aldehydes
Antifungal Agents
Antineoplastic Agents
Cell-Penetrating Peptides
Proteasome Inhibitors
Reactive Oxygen Species
Amphotericin B
DNA
Proteasome Endopeptidase Complex
Cisplatin