ABSTRACT
Emerging SARS-CoV-2 variants continue to cause waves of new infections globally. Developing effective antivirals against SARS-CoV-2 and its variants is an urgent task. The main protease (Mpro) of SARS-CoV-2 is an attractive drug target because of its central role in viral replication and its conservation among variants. We herein report a series of potent α-ketoamide-containing Mpro inhibitors obtained using the Ugi four-component reaction. The prioritized compound, Y180, showed an IC50 of 8.1 nM against SARS-CoV-2 Mpro and had oral bioavailability of 92.9%, 31.9% and 85.7% in mice, rats and dogs, respectively. Y180 protected against wild-type SARS-CoV-2, B.1.1.7 (Alpha), B.1.617.1 (Kappa) and P.3 (Theta), with EC50 of 11.4, 20.3, 34.4 and 23.7 nM, respectively. Oral treatment with Y180 displayed a remarkable antiviral potency and substantially ameliorated the virus-induced tissue damage in both nasal turbinate and lung of B.1.1.7-infected K18-human ACE2 (K18-hACE2) transgenic mice. Therapeutic treatment with Y180 improved the survival of mice from 0 to 44.4% (P = 0.0086) upon B.1.617.1 infection in the lethal infection model. Importantly, Y180 was also highly effective against the B.1.1.529 (Omicron) variant both in vitro and in vivo. Overall, our study provides a promising lead compound for oral drug development against SARS-CoV-2.
Subject(s)
COVID-19 Drug Treatment , SARS-CoV-2 , Angiotensin-Converting Enzyme 2 , Animals , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Disease Models, Animal , Dogs , Humans , Mice , RatsABSTRACT
The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continually poses serious threats to global public health. The main protease (Mpro) of SARS-CoV-2 plays a central role in viral replication. We designed and synthesized 32 new bicycloproline-containing Mpro inhibitors derived from either boceprevir or telaprevir, both of which are approved antivirals. All compounds inhibited SARS-CoV-2 Mpro activity in vitro, with 50% inhibitory concentration values ranging from 7.6 to 748.5 nM. The cocrystal structure of Mpro in complex with MI-23, one of the most potent compounds, revealed its interaction mode. Two compounds (MI-09 and MI-30) showed excellent antiviral activity in cell-based assays. In a transgenic mouse model of SARS-CoV-2 infection, oral or intraperitoneal treatment with MI-09 or MI-30 significantly reduced lung viral loads and lung lesions. Both also displayed good pharmacokinetic properties and safety in rats.
Subject(s)
Antiviral Agents/pharmacology , COVID-19 Drug Treatment , Coronavirus 3C Proteases/antagonists & inhibitors , Protease Inhibitors/pharmacology , Animals , Antiviral Agents/chemistry , Antiviral Agents/therapeutic use , COVID-19/pathology , COVID-19/virology , Cell Line , Cell Survival/drug effects , Chemokine CXCL10/metabolism , Disease Models, Animal , Drug Design , Humans , Interferon-beta/metabolism , Lung/immunology , Lung/pathology , Lung/virology , Mice , Mice, Transgenic , Oligopeptides , Proline/analogs & derivatives , Protease Inhibitors/chemistry , Protease Inhibitors/therapeutic use , Protease Inhibitors/toxicity , Rats , Rats, Sprague-Dawley , Viral Load/drug effects , Virus ReplicationABSTRACT
Autophagy inducers represent new promising agents for the treatment of a wide range of medical illnesses. However, safe autophagy inducers for clinical applications are lacking. Inhibition of cdc2-like kinase 1 (CLK1) was recently found to efficiently induce autophagy. Unfortunately, most of the known CLK1 inhibitors have unsatisfactory selectivity. Herein, we report the discovery of a series of new CLK1 inhibitors containing the 1H-[1,2,3]triazolo[4,5-c]quinoline scaffold. Among them, compound 25 was the most potent and selective, with an IC50 value of 2 nM against CLK1. The crystal structure of CLK1 complexed with compound 25 was solved, and the potency and kinase selectivity of compound 25 were interpreted. Compound 25 was able to induce autophagy in in vitro assays and displayed significant hepatoprotective effects in the acetaminophen (APAP)-induced liver injury mouse model. Collectively, due to its potency and selectivity, compound 25 could be used as a chemical probe or agent in future mechanism-of-action or autophagy-related disease therapy studies.
Subject(s)
Autophagy/drug effects , Chemical and Drug Induced Liver Injury/drug therapy , Protective Agents/chemistry , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/antagonists & inhibitors , Quinolines/chemistry , Triazoles/chemistry , Acetaminophen , Animals , Cell Line , Chemical and Drug Induced Liver Injury/pathology , Humans , Liver/drug effects , Liver/pathology , Male , Mice , Mice, Inbred C57BL , Models, Molecular , Protective Agents/chemical synthesis , Protective Agents/pharmacology , Quinolines/chemical synthesis , Quinolines/pharmacology , Stereoisomerism , Structure-Activity Relationship , Triazoles/chemical synthesis , Triazoles/pharmacologyABSTRACT
Two metabolites, cis-BP4, 5-dihydrodiol and cis-BP7, 8-dihydrodiol, were identified by high-performance liquid chromatography (HPLC) during the degradation of BaP by Bacillus-07 (BA-07). The two metabolites were hardly further metabolized for their toxicity to microorganism. To promote degradation of BaP and decrease accumulation of cis-BP4, 5-dihydrodiol and cis-BP7, 8-dihydrodiol, two methods (degradation only by BA-07, degradation by coupling the BA-07 and KMnO4) were compared. In addition, parameters of continued degradation of BaP and the two metabolites were optimized under the experiment conditions. The results showed that (1)the method of coupling the chemical oxidation and biodegradation (BA-07 and KMnO4) was better than only biodegradation (BA-07); (2) residue rate of cis-BP4, 5-dihydrodiol was higher than that of cis-BP7, 8-dihydrodiol when the samples were determined in the same time; (3)the effect of continued degradation was the best when the initial concentration of BaP was 40 microg/mL, pH value of the culture was 7.0, co-metabolic substrates was sodium succinate. Meanwhile, it was put forward that the method of coupling the chemical oxidation and biodegradation was effective on continued degradation of persistent organic contaminants in the environment.
