Linker-based design connecting antimicrobial peptides and glycans against Infection and Tumours

Objective

Antimicrobial resistance and cancer are two of the most urgent health challenges. In both cases, the impermeability and adaptability of cellular membranes contribute to poor drug uptake and favour drug resistance. Antimicrobial peptides (AMPs) are molecules that can efficiently disrupt these resistant membranes, but their lack of specificity often causes toxicity to healthy host cells, limiting their clinical application. This project, Link-IT, will develop a new molecular strategy in which AMPs are connected to targeting glycans through tuneable linkers. The systematic study of linkers connecting highly selective glycans and AMPs to enhance performance has not been investigated previously. This design aims to preserve the intrinsic membrane activity of AMPs while introducing receptor-guided specificity, thereby improving potency and selectivity. This project integrates three complementary work packages: (i) computational modelling to select AMP–linker–glycan constructs based on their stability and interactions with target receptors; (ii) chemical synthesis to generate selected candidates using peptide, glycan and linker chemistry; and (iii) biological testing in bacterial and cancer cell models to evaluate membrane disruption, receptor-mediated uptake and selectivity against healthy cells. Iterative feedback between these steps will establish structure–activity relationships. Expected outcomes will include new insights into how linker properties influence molecular recognition at membranes and the development of selective AMP–glycan conjugates with reduced toxicity. Beyond these immediate applications, Link-IT will provide a versatile platform for the design of future dual-targeting therapeutics.