Strategies for the design of biomimetic cell-penetrating peptides using AI-driven in silico tools for drug delivery.

Cell-penetrating peptides (CPP) have gained rapid attention over the last 25 years; this is attributed to their versatility, customisation, and 'Trojan horse' delivery that evades the immune system. However, the current CPP rational design process is limited, as it requires several rounds of peptide synthesis, prediction and wet-lab validation, which is expensive, time-consuming and requires extensive knowledge in peptide chemistry. Artificial intelligence (AI) has emerged as a promising alternative which can augment the design process, for example by determining physiochemical characteristics, secondary structure, solvent accessibility, disorder and flexibility, as well as predicting in vivo behaviour such as toxicity and peptidase degradation. Other more recent tools utilise supervised machine learning (ML) to predict the penetrative ability of an amino acid sequence. The use of AI in the CPP design process has the potential to reduce development costs and increase the chances of success with respect to delivery. This review provides a survey of in silico tools and AI platforms which can be utilised in the design process, and the key features that should be taken into consideration when designing next generation CPPs.