Machine learning tools for peptide bioactivity evaluation - Implications for cell culture media optimization and the broader cultivated meat industry.

Although bioactive peptides have traditionally been studied for their health-promoting qualities in the context of nutrition and medicine, the past twenty years have seen a steady increase in their application to cell culture media optimization. Complex natural sources of bioactive peptides, such as hydrolysates, offer a sustainable and cost-effective means of promoting cellular growth, making them an essential component of scaling-up cultivated meat production. However, the sheer diversity of hydrolysates makes product selection difficult, highlighting the need for functional characterization. Traditional wet-lab techniques for isolating and estimating peptide bioactivity cannot keep pace with peptide identification using high-throughput tools such as mass spectrometry, requiring the development and use of machine learning-based classifiers. This review provides a comprehensive list of available software tools to evaluate peptide bioactivity, classified and compared based on the algorithm, training set, functionality, and limitations of the underlying models. We curated independent test sets to compare the predictive performance of different models based on specific bioactivity classification relevant to promoting cell culture growth: antioxidant and anti-inflammatory. A comprehensive screening of all bioactivity classifiers revealed that while there are approximately fifty tools to elucidate antimicrobial activity and sixteen that predict anti-inflammatory activity, fewer tools are available for other functionalities related to cell growth - five that predict antioxidant activity and two for growth factor and/or cell signaling prediction. A thorough evaluation of the available tools revealed significant issues with sensitivity, specificity, and overall accuracy. Despite the overall interest in estimating peptide bioactivity, our work highlights key gaps in the broader adoption of existing software for the specific application of cell culture media optimization in the context of cultivated meat and beyond.