Nullomer derived anticancer peptides (NulloPs): differential lethal effects on normal and cancer cells in vitro
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Published on: August 25, 2021
Abdelkrim Alileche1, Jayita Goswami, William Bourland
1Department of Biological Sciences, Boise State University, 1910 University Drive, Boise, ID 83725, USA.
Abstract:
We demonstrate the first use of the nullomer (absent sequences) approach to drug discovery and development. Nullomers are the shortest absent sequences determined in a species, or group of species. By identifying the shortest absent peptide sequences from the NCBI databases, we screened several potential anti-cancer peptides. In order to improve cell penetration and solubility we added short poly arginine tails (5Rs), and initially solubilized the peptides in 1M trehalose. The results for one of the absent sequences 9R (RRRRRNWMWC), and its scrambled version 9S1R (RRRRRWCMNW) are reported here. We refer to these peptides derived from nullomers as PolyArgNulloPs. A control PolyArgNulloP, 124R (RRRRRWFMHW), was also included. The lethal effects of 9R and 9S1R are mediated by mitochondrial impairment as demonstrated by increased ROS production, ATP depletion, cell growth inhibition, and ultimately cell death. These effects increase over time for cancer cells with a concomitant drop in IC-50 for breast and prostate cancer cells. This is in sharp contrast to the effects in normal cells, which show a decreased sensitivity to the NulloPs over time.
Insights
We introduce nullomers, shortest absent sequences, for novel drug discovery. These peptides show potent anti-cancer effects by impairing mitochondria, offering a new therapeutic strategy.
Area of Science:
- Biotechnology
- Drug Discovery
- Molecular Biology
Background:
- Nullomers represent the shortest absent sequences within a species' genome.
- Identifying and utilizing nullomers offers a novel avenue for therapeutic development.
Purpose of the Study:
- To explore the nullomer approach for drug discovery and development.
- To synthesize and evaluate novel anti-cancer peptides derived from nullomers (PolyArgNulloPs).
Main Methods:
- Screening NCBI databases for shortest absent peptide sequences (nullomers).
- Synthesizing nullomer-derived peptides with poly arginine tails (PolyArgNulloPs) and trehalose solubilization.
- Assessing peptide efficacy through cell viability assays, ROS production, and ATP depletion measurements.
Main Results:
- Two nullomer-derived peptides, 9R and 9S1R, demonstrated significant anti-cancer activity.
- Mitochondrial impairment, evidenced by increased ROS and ATP depletion, mediated the cytotoxic effects.
- Cancer cells showed increased sensitivity over time, with decreased IC-50 values for breast and prostate cancer cells.
- Normal cells exhibited reduced sensitivity to the PolyArgNulloPs.
Conclusions:
- The nullomer approach is a viable strategy for identifying novel anti-cancer drug candidates.
- PolyArgNulloPs exhibit potent and selective cytotoxicity against cancer cells through mitochondrial disruption.
- Nullomer-based therapeutics demonstrate promising differential effects on cancer versus normal cells.
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