The global impact of Coronavirus disease-2019 (COVID-19) on individuals and healthcare systems has led to extensive research on the biological properties of the causative virus, severe acute respiratory syndrome-Coronavirus 2 (SARS-CoV-2). COVID-19 manifests primarily as a respiratory disease but can affect multiple organs, resulting in a variety of biochemical and clinical sub-phenotypes. Prolonged immune system stimulation and metabolic disruptions contribute to persistent symptoms known as long-Covid or Post Acute COVID-19 Syndrome (PACS). Biomarkers, including amino acids, lipids, cytokines, and pro-inflammatory markers, have been identified to assess the onset, progression, and recovery of COVID-19. Metabotyping the patient journey is crucial for understanding the immuno-metabolic consequences of SARS-CoV-2 infection.
We present compelling evidence for the existence of an evolutionary adaptive response to viral agents such as SARS-CoV-2, that results in the human in vivo biosynthesis of a family of compounds with potential antiviral activity. Using nuclear magnetic resonance (NMR) spectroscopy, we detected a characteristic spin-system motif indicative of the presence of an panel of 12 urinary and serum metabolites during the acute viral phase. The structure of eight of the nucleoside analogues was elucidated (six of which have not previously been reported in human biofluids), and subsequently confirmed by total-synthesis and matrix spiking. The molecular structures of the nucleoside analogues and their correlation with an array of serum cytokines, including IFN-α2, IFN-γ and IL-10, suggest an association with the viperin enzyme contributing to an endogenous innate immune defense mechanism against viral infection. Their high concentration in urine and their structural similarity with known anti-virals, some of which are associated with serious secondary effects, raise questions about their potential long-term consequences on health and their potential role in PACS.