Hemoglobin as a Molecular Glue: Toward Potent Inhibition of HbS Polymerization in Sickle Cell Disease

Sickle cell disease (SCD), a monogenic disorder arising from a single point mutation in the β-globin gene, continues to pose a significant global health burden despite advances in supportive care. This mutation drives the formation of hemoglobin S (HbS) polymers under deoxygenated conditions, causing erythrocyte sickling, vaso-occlusive crises, and multi-organ complications. Current therapies, such as hydroxyurea and voxelotor, provide only partial symptomatic relief, underscoring the urgent need for transformative strategies. This review highlights the molecular glue paradigm, a novel approach that repurposes hemoglobin itself as a therapeutic scaffold. By integrating high-resolution structural insights from cryo-electron microscopy and predictive modeling via artificial intelligence, engineered hemoglobin variants can be rationally designed to inhibit polymerization, stabilizing non-pathogenic conformations and preventing fiber formation. These molecular glues, generated through gene editing or synthetic biology, offer a cell-intrinsic, high-concentration mechanism to counteract HbS polymerization, potentially overcoming the limitations of current therapies. We examine the key challenges in translating this paradigm, including precise structural characterization of polymerization intermediates, efficient intracellular delivery to erythrocytes, temporal regulation under hypoxic conditions, and the mitigation of immunogenicity.