Acknowledgements: Acknowledgements: We thank The Spinnaker Health Research Foundation, WA, The McCusker Foundation, WA, The Western Australian State Government and the Medical Research Future Fund (EPCD000037 and MRF2014349) for financial support. We thank the Department of Jobs, Tourism, Science and Innovation, Government of a Western Australian Premier's Fellowship for RLL and the ARC for Laureate Fellowship funding for EH. JW thanks Ministerio de Ciencia, Tecnología e Innovación (Minciencias), Ministerio de Educación Nacional, Ministerio de Industria, Comercio y Turismo e ICETEX (792–2017) 2a Convocatoria Ecosistema Científico - Colombia Científica para la Financiación de Proyectos de I + D + i), World Bank and Vicerrectoría de Investigaciones, Pontificia Universidad Javeriana, Bogotá, Colombia (contract no. FP44842 - 221-2018). We gratefully thank the Werner Siemens Imaging Center under direction of Prof. Bernd Pichler for supporting this project as well as Aditi Kulkarni and Daniele Bucci for excellent technical assistance. JMW, GBE and LDH thank the New Zealand Ministry of Business Innovation & Employment for support (Endeavour Fund program contract UOOX1904 (NZ)).

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 extended panel of urinary and serum metabolites during the acute viral phase. The structure of eight of nucleoside analogues was elucidated (six of which have not previously been reported in human urine), 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.