Improvement of the performance of anticancer peptides using a drug repositioning pipeline

Abstract

The use of anticancer peptides (ACPs) as an alternative/complementary strategy to conventional chemotherapy treatments has been shown to decrease drug resistance and/or severe side effects. However, the efficacy of the positively-charged ACP is inhibited by elevated levels of negatively-charged cell-surface components which trap the peptides and prevent their contact with the cell membrane. Consequently, this decreases ACP-mediated membrane pore formation and cell lysis. Negatively-charged heparan sulphate (HS) and chondroitin sulphate (CS) have been shown to inhibit the cytotoxic effect of ACPs.In this study, we propose a strategy to promote the broad utilization of ACPs. In this context, we developed a drug repositioning pipeline to analyse transcriptomics data generated for four different cancer cell lines (A549, HEPG2, HT29, and MCF7) treated with hundreds of drugs in the LINCS L1000 project. Based on previous studies identifying genes modulating levels of the glycosaminoglycans (GAGs) HS and CS at the cell surface, our analysis aimed at identifying drugs inhibiting genes correlated with high HS and CS levels. As a result, we identified six chemicals as likely repositionable drugs with the potential to enhance the performance of ACPs. The codes in R and Python programming languages are publicly available in https://github.com/ElyasMo/ ACPs_HS_HSPGs_CS.As a conclusion, these six drugs are highlighted as excellent targets for synergistic studies with ACPs aimed at lowering the costs associated with ACP-treatment.

Advancing Peptide-Based Cancer Therapy with AI: In-Depth Analysis of State-of-the-Art AI Models

“…Cancer is a caused by genetic mutations that result in the uncontrolled growth and spread of infiltrative abnormal cells that destroy normal tissues throughout the body. − Despite considerable advances in cancer therapy, traditional treatments remain associated with high costs, deleterious side effects, high recurrence, and low success rates. However, these limitations have led to increasing interest in developing novel agents including therapeutic peptides to treat cancer. − Such peptides have been discovered and developed through in vitro research and peptide–protein interaction interfaces, designed with the aid of computations, and identified using mass spectrometry. − Short anticancer peptides (ACPs) comprising 10–60 amino acids inhibit the growth or migration of tumor cells and the formation of tumor blood vessels. , These peptides have a low propensity to resistance and are not toxic to healthy cells. , They also have a quick time to market, high selectivity, and minimal attrition and are effective, safe, and well tolerated. Traditional experimental approaches to identifying ACPs and peptide abundance sequences generated in the postgenomics era have important limitations .…”

“…13,14 These peptides have a low propensity to resistance and are not toxic to healthy cells. 15,16 They also have a quick time to market, high selectivity, and minimal attrition and are effective, safe, and well tolerated. Traditional experimental approaches to identifying ACPs and peptide abundance sequences generated in the postgenomics era have important limitations.…”

Drug repositioning for immunotherapy in breast cancer using single-cell and spatial transcriptomics analysis

“…These chemicals have known modes of action and targets for another indication. Thus, exploring them minimizes the cost of therapy, time and risk [14][15][16][17].…”