Captopril

To identify drugs and reagents that modulate the 332 host factors interacting with SARS-CoV-2-HEK293T/17 (MiST >= 0.70), we used two approaches: 1) a chemoinformatic analysis of open-source chemical databases and 2) a target- and pathway-specific literature search, drawing on specialist knowledge within our group. Chemoinformatically, we retrieved 2,472 molecules from the IUPHAR/BPS Guide to Pharmacology (2020–3-12)^{56 (link)} (Supplementary Table 7) that interacted with 30 human “prey” proteins (38 approved, 71 in clinical trials), and found 10,883 molecules (95 approved, 369 in clinical trials) from the ChEMBL25 database^{77 (link)} (Supplementary Table 8). For both approaches, molecules were prioritized on their FDA approval status, activity at the target of interest better than 1 μM, and commercial availability, drawing on the ZINC database^{78 (link)}. FDA approved molecules were prioritized except when clinical candidates or preclinical research molecules had substantially better selectivity or potency on-target. In some cases, we considered molecules with indirect mechanisms of action on the general pathway of interest based solely on literature evidence (e.g., captopril modulates ACE2 indirectly via its direct interaction with Angiotensin Converting Enzyme, ACE). Finally, we predicted 6 additional molecules (2 approved, 1 in clinical trials) for proteins with MIST scores between 0.7–0.6 to viral baits (Supplementary Tables 4 and 5). Complete methods can be found here (https://github.com/momeara/BioChemPantry/tree/master/vignette/COVID19).

Adult C57BL/6J mice were obtained from Jackson Laboratory at 8 weeks of age, placed on a standard mouse chow diet and water ad libitum, and housed in a temperature-controlled environment under an alternating 12-hour light-dark cycle. All animal handling procedures adhered strictly to the approved guidelines of the Institutional Animal Care and Use Committee. A total of 16 mice (mean weight, 26.3±1.7 g) were randomly assigned to 1 of the following 3 groups: a group that underwent open thoractomy without coronary ligation (“sham”, N=5); a group that underwent permanent left anterior descending artery (LAD) ligation without subsequent treatment (“MI”, N=6); and, a group that underwent permanent LAD ligation followed by oral administration of an angiotensin converting enzyme inhibitor (ACEi) (captopril 20 mg/kg/day) in the drinking water starting on day 7 following surgery (“MI+ACEi”, N=5). Coronary ligation was performed as previously described.^{10 (link)} Echocardiography was performed on all mice under light sedation (1% isoflurane in oxygen) prior to surgery (baseline) and at 1 week following surgery (prior to starting any treatment with ACEi), at 3 weeks, and at 7 weeks following surgery. Echocardiography was performed using a 18–38 MHz linear-array transducer with a digital ultrasound system (Vevo 2100 Imaging System, VisualSonics, Toronto, Canada). Standard parasternal long- and short-axis views were obtained during each echocardiographic exam. Conventional and novel echocardiographic image measurements were performed offline. All image acquisitions and offline measurements included in the present analysis were conducted by a single investigator who was blinded to animal groups. At 7 weeks, mice were sacrificed for pathologic assessment of cardiac remodeling and infarct size.

Rats were anesthetized with 3–5% isoflurane for blood draws by retro-orbital bleeds conducted by an experienced technician. At 70 days three rats were lost under anesthesia and eliminated (censored) from the study [11.5 Gy + enalapril 18 mg/m²/day (2) and 11.5 Gy + captopril 176 mg/m²/day (1)]. The BUN was assayed from serum as described previously (19 (link)) using a urease-nitroprusside colorimetric assay. BUN values were expressed as mg/dl of serum and median with 25–75% ranges were plotted and used for statistical analysis. Irradiated rats with BUN >120 mg/dl were previously confirmed to have renal damage (18 (link)).