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Eur J Med Chem ; 244: 114853, 2022 Dec 15.
Article in English | MEDLINE | ID: covidwho-2068912


SARS-CoV-2 caused worldwide the current outbreak called COVID-19. Despite multiple countermeasures implemented, there is an urgent global need for new potent and efficient antiviral drugs against this pathogen. In this context, the main protease (Mpro) of SARS-CoV-2 is an essential viral enzyme and plays a pivotal role in viral replication and transcription. Its specific cleavage of polypeptides after a glutamine residue has been considered as a key element to design novel antiviral drugs. Herein, we reported the design, synthesis and structure-activity relationships of novel α-ketoamides as covalent reversible inhibitors of Mpro, exploiting the PADAM oxidation route. The reported compounds showed µM to nM activities in enzymatic and in the antiviral cell-based assays against SARS-CoV-2 Mpro. In order to assess inhibitors' binding mode, two co-crystal structures of SARS-CoV-2 Mpro in complex with our inhibitors were solved, which confirmed the covalent binding of the keto amide moiety to the catalytic Cys145 residue of Mpro. Finally, in order to interrogate potential broad-spectrum properties, we assessed a selection of compounds against MERS Mpro where they showed nM inhibitory potency, thus highlighting their potential as broad-spectrum coronavirus inhibitors.

COVID-19 , SARS-CoV-2 , Humans , Coronavirus 3C Proteases , COVID-19/drug therapy , Protease Inhibitors/pharmacology , Protease Inhibitors/chemistry , Viral Nonstructural Proteins , Cysteine Endopeptidases/metabolism , Antiviral Agents/pharmacology , Antiviral Agents/chemistry , Molecular Docking Simulation
ChemMedChem ; 15(11): 907-932, 2020 06 04.
Article in English | MEDLINE | ID: covidwho-108817


The COVID-19 pandemic caused by SARS-CoV-2 infection is spreading at an alarming rate and has created an unprecedented health emergency around the globe. There is no effective vaccine or approved drug treatment against COVID-19 and other pathogenic coronaviruses. The development of antiviral agents is an urgent priority. Biochemical events critical to the coronavirus replication cycle provided a number of attractive targets for drug development. These include, spike protein for binding to host cell-surface receptors, proteolytic enzymes that are essential for processing polyproteins into mature viruses, and RNA-dependent RNA polymerase for RNA replication. There has been a lot of ground work for drug discovery and development against these targets. Also, high-throughput screening efforts have led to the identification of diverse lead structures, including natural product-derived molecules. This review highlights past and present drug discovery and medicinal-chemistry approaches against SARS-CoV, MERS-CoV and COVID-19 targets. The review hopes to stimulate further research and will be a useful guide to the development of effective therapies against COVID-19 and other pathogenic coronaviruses.

Antiviral Agents/therapeutic use , Chemistry, Pharmaceutical/trends , Coronavirus Infections/drug therapy , Drug Development , Pneumonia, Viral/drug therapy , Antiviral Agents/pharmacology , COVID-19 , Drug Discovery , Humans , Models, Molecular , Pandemics , Protease Inhibitors/therapeutic use