Identification of pharmacological inducers of a reversible hypometabolic state for whole organ preservation

Abstract

An injectable 'biostasis' drug that could slow organ injury by inducing a state of suspended animation through reversible slowing of metabolic processes would have great value for organ preservation and treatment of badly injured patients at the point-of-care. Using whole-organism screening of metabolism, mobility, and development in Xenopus, we identified an existing drug, SNC80, that rapidly and reversibly slows biochemical and metabolic activities while preserving cell and tissue viability, independently of its known delta opioid receptor modulating activity. Metabolic suppression was also achieved using SNC80 in cultured cells and microfluidic human organs-on-chips, as well as in explanted whole porcine hearts and limbs, demonstrating the cross-species relevance of this approach and potential clinical relevance for surgical transplantation. Thermal proteome profiling revealed that SNC80 targets the NCX1/EEAT1 membrane transport system and chemical modulation of NCX1 induces biostasis in non-hibernating Xenopus tadpoles. Molecular induction of biostasis may offer a new therapeutic approach for organ preservation, trauma management, and enhancing patient survival in remote and low-resource locations.