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

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.