SGLT2‐Inhibition reverts urinary peptide changes associated with severe COVID‐19: An in‐silico proof‐of‐principle of proteomics‐based drug repurposing

Abstract

Severe COVID-19 is reflected by significant changes in urine peptides. Based on this observation, a clinical test predicting COVID-19 severity, CoV50, was developed and registered as in vitro diagnostic in Germany. We have hypothesized that molecular changes displayed by CoV50, likely reflective of endothelial damage, may be reversed by specific drugs. Such an impact by a drug could indicate potential benefits in the context of COVID-19. To test this hypothesis, urinary peptide data from patients without COVID-19 prior to and after drug treatment were collected from the human urinary proteome database. The drugs chosen were selected based on availability of sufficient number of participants in the dataset (n>20) and potential value of drug therapies in the treatment of COVID-19 based on reports in the literature. In these participants without COVID-19, spironolactone did not demonstrate a significant impact on CoV50 scoring. Empagliflozin treatment resulted in a significant change in CoV50 scoring, indicative of a potential therapeutic benefit. The study serves as a proof-of-principle for a drug repurposing approach based on human urinary peptide signatures. The results support the initiation of a randomised control trial testing a potential positive effect of empagliflozin for severe COVID-19, possibly via endothelial protective mechanisms.

Exploratory Study Analyzing the Urinary Peptidome of T2DM Patients Suggests Changes in ECM but Also Inflammatory and Metabolic Pathways Following GLP-1R Agonist Treatment

“…The standard operating protocols describing urine sample preparation and extraction of peptides followed in this study have been applied in numerous studies, as reviewed previously [58]. The CE-MS analysis was conducted as described in detail by Zurbig et al [59], utilizing a P/ACE MDQ capillary electrophoresis system (Beckman Coulter, Fullerton, CA, USA) coupled with a Micro-TOF II MS (Bruker Daltonic, Bremen, Germany) instrument.…”

Application of Urinary Peptide-Biomarkers in Trauma Patients as a Predictive Tool for Prognostic Assessment, Treatment Interventions, and Intervention Timing: Prospective Nonrandomized Pilot Study

“…The COV50 classifier, developed during the COVID-19 pandemic was able to predict the incidence of death and disease progression in infected patients (25). It also demonstrated significant prediction of mortality in patients without SARS-CoV-2 infection in the ICU but also in the general population (25,26).…”

“…Biomarkers such as AKI204, which is useful for predicting acute kidney injury (AKI) in ICU patients (20), and CKD273, which is a biomarker for the detection of chronic kidney disease (CKD), can predict worsening of kidney function (21) or cardiovascular outcome (22) and may be good biomarkers for both predicting kidney damage in polytraumatized patients and providing the time to start renal replacement therapy early (23,24). The COV50 classifier, developed during the COVID-19 pandemic was able to predict the incidence of death and disease progression in infected patients (25). It also demonstrated significant prediction of mortality in patients without SARS-CoV-2 infection in the ICU but also in the general population (25,26).…”

Reproducibility Evaluation of Urinary Peptide Detection Using CE-MS

“…Given the fact that urinary peptides are reflective of the health status of individuals, CE-MS has been applied mainly in the context of biomarker research, to define biomarkers for early detection of disease [ 21 ], prediction of disease progression [ 22 , 23 ], treatment response and patient stratification in the clinical trial [ 24 ]. Among the most recent applications, a proof-of-principle study for the use of CE-MS in the drug repurposing field was published, showing the potential of sodium/glucose cotransporter 2 inhibitors to combat COVID-19 [ 25 ]. In addition to reports on clinical applications, investigations of the technical aspects concerning robustness and comparability with other techniques have been performed [ 4 , 9 ], supporting the applicability of CE-MS as a tool for clinical purposes.…”