Note: Bladder cancer therapy using a conformationally fluid tumoricidal peptide complex
Note: Bladder cancer therapy using a conformationally fluid tumoricidal peptide complex
Doi: 10.1038/s41467-021-23748-y
Overall
Define a peptide-based molecular approach for targeting and killing tumor cells
Evidence of its clinical application (NCT03560479)
Peptide -- > 39 residue showed to gain lethality for killing tumor cells by forming oleic acid complexes (alpha1-oleate)
Using NMR to study the structural complex of alpha1-oleate
Lipid core is surrounded by alpha-helical peptide motif
Clinical trial
Non-muscle invasive bladder cancer
Shred tumor cells contain alpha1-oleate -- no side effects
Treated tumor -- demonstrate apoptosis
Toxicity comes from the folding status
Formation of amorphous aggregates and amyloid fibrils
Antimicrobial peptide
the ability to destabilize lipid bilayers has been proposed to reside in the three dimensional conformation rather than the amino acid sequence
Function of alpha-lactalbumin
In its native state, the protein serves as a substrate specifier in the lactose-synthase complex -- by this reaction it makes milk more fluidity.
This study showed peptide-based molecule to kill cancer cells, previous study used the whole proteins complexed with oleic acid to cancer cells
Synthesis peptide used in this study
1-39 -- namely alpha1
Forming alpha1-oleate
After binding to oleate -- induced structural change
40-80 -- namely beta
Binding to oleate -- did not induce structural change
No tumoricidal activity
Cancer cell lines
Human lung cancer
Kidney carcinoma cells
Murine bladder cancer cells
They also compare the alpha1 with SAR1 peptide domain from COPII -- and show SAR1+oleic acid had tumoricidal activity
Naked peptide (both alpha1 and beta), beta+oleate -- inactive for tumoricidal activity
Tumor being killed
Tumor not being killed
Computational stimulation -- A contact probability analysis revealed that the interactions
between alpha1 or sar1alpha and oleate were mainly hydrophobic.
Toxicity for bladder tissue was not detected at concentrations ranging from 1.7 to 17 mM
Clinical trial
2 ARMS
Alpha1-oleate (1.7 mM)
Placebo (PBS)
Each 30 ml
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