Poly(glutamic acid-block-tyrosine) peptides designed for gastrointestinal drug adsorption.

Drug overdose remains a major public health challenge, particularly for non-opioid substances that lack effective antidotes and are often treated through gastrointestinal decontamination with activated charcoal. While activated charcoal is broadly effective, its use is associated with aspiration risks and gastrointestinal complications. Here, we report a class of synthetic poly(glutamic acid-block-tyrosine) (EY) peptide adsorbent materials designed as biocompatible, tuneable alternatives for gastrointestinal drug adsorption. EY polypeptides were synthesized via N-carboxyanhydride ring-opening polymerization with systematically varied tyrosine block lengths to investigate how amino acid composition and length govern adsorption. Adsorption kinetics and capacity were evaluated under simulated gastric (pH 1.2) and intestinal (pH 6.8) conditions for clinically relevant drugs commonly implicated in overdose: amitriptyline (AMI), bupropion (BUP), hydroxychloroquine (HCQ), and strychnine (STR). Increasing tyrosine content enhanced drug uptake, with the top-performing formulation (E30Y129) achieving high adsorption capacities and binding affinities comparable to reported adsorbent biopolymers and competitive with activated charcoal for certain drugs. Langmuir isotherm analysis revealed maximum adsorption capacities of 40-238 mg g-1 and binding affinities up to 0.214 L g-1, with adsorption behavior dependent on drug characteristics. Exploratory fed-state experiments demonstrated that adsorbent properties are retained in the presence of a complex nutrient matrix and vary depending on drug properties. Preliminary enzyme degradation studies indicated gradual proteolysis under gastrointestinal conditions, and cytocompatibility assays with fibroblasts and macrophages showed no overt toxicity across relevant concentrations. Collectively, these results demonstrate that synthetic polypeptides can be engineered to achieve efficient, clinically relevant drug adsorption while offering advantages in biocompatibility, degradability, and tunability. This work establishes a foundation for next-generation gastrointestinal decontamination materials beyond activated charcoal.