ObjectiveWe assessed whether famotidine improved inflammation and symptomatic recovery in outpatients with mild to moderate COVID-19.DesignRandomised, double-blind, placebo-controlled, fully remote, phase 2 clinical trial (NCT04724720) enrolling symptomatic unvaccinated adult outpatients with confirmed COVID-19 between January 2021 and April 2021 from two US centres. Patients self-administered 80 mg famotidine (n=28) or placebo (n=27) orally three times a day for 14 consecutive days. Endpoints were time to (primary) or rate of (secondary) symptom resolution, and resolution of inflammation (exploratory).ResultsOf 55 patients in the intention-to-treat group (median age 35 years (IQR: 20); 35 women (64%); 18 African American (33%); 14 Hispanic (26%)), 52 (95%) completed the trial, submitting 1358 electronic symptom surveys. Time to symptom resolution was not statistically improved (p=0.4). Rate of symptom resolution was improved for patients taking famotidine (p<0.0001). Estimated 50% reduction of overall baseline symptom scores were achieved at 8.2 days (95% CI: 7 to 9.8 days) for famotidine and 11.4 days (95% CI: 10.3 to 12.6 days) for placebo treated patients. Differences were independent of patient sex, race or ethnicity. Five self-limiting adverse events occurred (famotidine, n=2 (40%); placebo, n=3 (60%)). On day 7, fewer patients on famotidine had detectable interferon alpha plasma levels (p=0.04). Plasma immunoglobulin type G levels to SARS-CoV-2 nucleocapsid core protein were similar between both arms.ConclusionsFamotidine was safe and well tolerated in outpatients with mild to moderate COVID-19. Famotidine led to earlier resolution of symptoms and inflammation without reducing anti-SARS-CoV-2 immunity. Additional randomised trials are required.

The substrate promiscuity of microbial transglutaminase (mTG) has been exploited in various applications in biotechnology,inparticular for the attachment of alkylamines to glutamine-containing peptides and proteins.H ere,w e expand the substrate repertoire to include hydrazines,h ydrazides,a nd alkoxyamines,resulting in the formation of isopeptide bonds with varied susceptibilities to hydrolysis or exchange by mTG.F urthermore,w ed emonstrate that simple unsubstituted hydrazine and dihydrazides can be used to install reactive hydrazide handles onto the side chain of internal glutamine residues.The distinct hydrazide handles can be further coupled with carbonyls,i ncluding ortho-carbonylphenylboronic acids, to form site-specific and functional bioconjugates with tunable hydrolytic stability.T he extension of the substrate scope of mTG beyond canonical amines thus substantially broadens the versatility of the enzyme,providing anew approach to facilitate novel applications. Scheme 1. Transamidation reaction catalyzed by microbial transglutaminase (mTG) using an amine or an a-effect nucleophile a) hydrazine, b) hydrazide, or c) alkoxyaminea sthe acyl acceptor substrate.

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The secreted protein Cystatin C (CyC) is a cysteine protease inhibitor of incompletely characterized biomedical function, used clinically for estimation of glomerular filtration rate. Plasma CyC is elevated in many patients, especially when they receive glucocorticoid (GC) treatment. Here we empirically connect GCs with systemic regulation of CyC. First, we leveraged genome-wide association and structural equation modeling to determine the genetics of the latent trait CyC production in UK Biobank. Using multi-modal genomic, transcriptional, and experimental approaches, we demonstrated that CyC is a direct target of GC receptor, with GC-responsive CyC secretion exhibited by macrophages and cancer cells in vitro. Elevated serum CyC levels were positively correlated with GC levels in a murine model of cancer progression. Consistent with the coupling of CyC levels to GC signaling in a disease relevant manner, CyC predicted elevated all-cause and cancer-specific mortality in humans. These associations were orthogonally confirmed by a polygenic score (PGS) capturing germline predisposition to CyC production. This PGS predicted checkpoint immunotherapy failure in a combined clinical trial cohort of 685 metastatic cancer patients, with available germline exome sequencing. Taken together, our results demonstrate that CyC captures biomedically-relevant variations in endogenous GC activity, raising the possibility that CyC may be a direct effector of GC-induced immunosuppression and therefore a target for combination cancer immunotherapy.