Conjugates of Heme and Intrinsically Disordered Peptides toward the Development of Synthetic Artificial Oxygen Carriers

Artificial oxygen carriers (AOCs) remain an unmet medical need in clinical practice. While hemoglobin is relatively safe within red blood cells, its release into circulation causes complications due to hemoglobin degradation forming toxic hemin. Here we report the design and synthesis of a novel heme-intrinsically disordered peptide (Heme-IDP) conjugate as a potential prototype for next-generation AOCs. Heme-IDP demonstrates markedly reduced cytotoxicity compared with free hemin and protoporphyrin IX (PPIX). Fluorescence imaging further indicates that negatively charged IDP significantly reduces PPIX cellular uptake, contributing to improved biocompatibility of Heme-IDP. The use of d-enantiomeric IDP sequences enhances peptide stability. Spectroscopic analyses confirm that Heme-IDP retains the ability for axial binding. These results highlight the potential of d-peptide-based IDP to mitigate the intrinsic toxicity associated with heme derivatives, offering a promising new direction for the development of safer and more biocompatible AOCs.