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The virus replication and lung inflammation are basic targets for COVID-19 treatment. To effectively treat COVID-19, the best chemical drug should combine inhibition of SARS-CoV-2 replication and direct suppression of inflammatory cytokine expression together. Our SARS-CoV-2 main protease (Mpro) crystal structure studies revealed Au(I), derived from auranofin (AF) or gold cluster (GA), could specifically bind thiolate of Cys145 of SARS-CoV-2 Mpro. GA or AF could well inhibit Mpro activity and significantly decrease SARS-CoV-2 replication in cell. Cell studies showed that either AF or GA could down-regulate NFκB pathway, therefore significantly inhibit inflammatory cytokine level of IL-6, IL-1β, TNF-α in macrophage and bronchial epithelial cell, respectively. The lung viral load in GA treated COVID-19 mice (15mg/kg.bw) is significantly lower than that in normal saline (NS, 0.9% NaCl) treated COVID-19 mice, and pathological studies revealed GA treatment (score ~1.8) significantly reduced lung inflammatory injury compared with NS treated COVID-19 mice (score ~3). After normal mice were treated by GA (15mg/kg), the Au ingredient well distributed into lungs and there are no pathological changes in main organs when compared with control mice. The toxicity results revealed GA is more safety than auranofin for cell/mice/rat. The rat pharmacokinetics studies show GA is with high bioavailability (> 90%) in vivo.

Our studies implied the golden compounds may be more effective against COVID 19 as they synergy inhibit SARS COV 2 replication and down regulation inflammation cytokine level. Our crystal structure studies firstly revealed Au (I) ions, derived from auranofin (AF) or gold cluster (GA), covalently bind sulfur atom of Cys145 and Cys156 of Mpro of SARS COV 2. The auranofin or gold cluster well inhibit Mpro activity in vitro. Auranofin or gold cluster could well suppress inflammation cytokine level of IL 6, IL 1β, TNF α via down regulation NF κB activation in macrophage. The cell viability and rat toxicity studies show gold cluster is more safety when compared FDA approved auranofin. The rat pharmacokinetic studies of gold cluster revealed its good bioavailability.