In Global challenges (Hoboken, NJ)
Anticancer peptides (ACPs) are rising as a new strategy for cancer therapy. However, traditional laboratory screening to find and identify novel ACPs from hundreds to thousands of peptides is costly and time consuming. Here, a sequential procedure is applied to identify candidate ACPs from a computer-generated peptide library inspired by alpha-lactalbumin, a milk protein with known anticancer properties. A total of 2688 distinct peptides, 5-25 amino acids in length, are generated from alpha-lactalbumin. In silico ACP screening using the physicochemical and structural filters and three machine learning models lead to the top candidate peptides ALA-A1 and ALA-A2. In vitro screening against five human cancer cell lines supports ALA-A2 as the positive hit. ALA-A2 selectively kills A549 lung cancer cells in a dose-dependent manner, with no hemolytic side effects, and acts as a cell penetrating peptide without membranolytic effects. Sequential window acquisition of all theorical fragment ions-proteomics and functional validation reveal that ALA-A2 induces autophagy to mediate lung cancer cell death. This approach to identify ALA-A2 is time and cost-effective. Further investigations are warranted to elucidate the exact intracellular targets of ALA-A2. Moreover, these findings support the use of larger computational peptide libraries built upon multiple proteins to further advance ACP research and development.
Lerksuthirat Tassanee, On-Yam Pasinee, Chitphuk Sermsiri, Stitchantrakul Wasana, Newburg David S, Morrow Ardythe L, Hongeng Suradej, Chiangjong Wararat, Chutipongtanate Somchai
2023-Mar
SWATH‐MS, anticancer peptides, cytotoxic screening, drug discovery, lung adenocarcinoma, machine learning, peptide library
