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Biochem J ; 478(13): 2517-2531, 2021 07 16.
Article in English | MEDLINE | ID: covidwho-1290988


The COVID-19 pandemic has emerged as the biggest life-threatening disease of this century. Whilst vaccination should provide a long-term solution, this is pitted against the constant threat of mutations in the virus rendering the current vaccines less effective. Consequently, small molecule antiviral agents would be extremely useful to complement the vaccination program. The causative agent of COVID-19 is a novel coronavirus, SARS-CoV-2, which encodes at least nine enzymatic activities that all have drug targeting potential. The papain-like protease (PLpro) contained in the nsp3 protein generates viral non-structural proteins from a polyprotein precursor, and cleaves ubiquitin and ISG protein conjugates. Here we describe the expression and purification of PLpro. We developed a protease assay that was used to screen a custom compound library from which we identified dihydrotanshinone I and Ro 08-2750 as compounds that inhibit PLpro in protease and isopeptidase assays and also inhibit viral replication in cell culture-based assays.

Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Coronavirus Papain-Like Proteases/antagonists & inhibitors , Drug Evaluation, Preclinical , SARS-CoV-2/enzymology , Small Molecule Libraries/pharmacology , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/pharmacology , Alanine/analogs & derivatives , Alanine/pharmacology , Aniline Compounds/pharmacology , Animals , Benzamides/pharmacology , Chlorocebus aethiops , Coronavirus Papain-Like Proteases/genetics , Coronavirus Papain-Like Proteases/isolation & purification , Coronavirus Papain-Like Proteases/metabolism , Drug Synergism , Enzyme Assays , Flavins/pharmacology , Fluorescence Resonance Energy Transfer , Furans/pharmacology , High-Throughput Screening Assays , Inhibitory Concentration 50 , Naphthalenes/pharmacology , Phenanthrenes/pharmacology , Quinones/pharmacology , Reproducibility of Results , SARS-CoV-2/drug effects , SARS-CoV-2/growth & development , Small Molecule Libraries/chemistry , Vero Cells , Virus Replication/drug effects
J Nat Prod ; 84(2): 436-443, 2021 02 26.
Article in English | MEDLINE | ID: covidwho-1072094


A new axial chiral binaphtoquinone, hypocrellone (1), and a new perylenequinone, hypomycin F (2), were isolated from the stromata of Hypocrella bambusae, together with five known compounds, 3-7. The structures of 1 and 2 were assigned by spectroscopic and HRESIMS data analyses. The axial chirality of 1 was determined by electronic circular dichroism data analysis, and the absolute configurations of 2 and 3 were determined by X-ray crystallography. The axial chirality of 7 was determined by UV-induced photooxidation from 4. Compounds 1, 4, and 5 showed inhibitory activity against pseudotyped SARS-CoV-2 infection in 293T-ACE2 cells with IC50 values of 0.17, 0.038, and 0.12 µM. Compounds 4 and 5 were also active against live SARS-CoV-2 infection with EC50 values of 0.22 and 0.21 µM, respectively. Further cell-cell fusion assays, surface plasmon resonance assays, and molecular docking studies revealed that 4 and 5 could bind with the receptor-binding domain of SARS-CoV-2 S protein to prevent its interaction with human angiotensin-converting enzyme II receptor. Our results revealed that 4 and 5 are potential SARS-CoV-2 entry inhibitors.

Hypocreales/chemistry , Naphthoquinones/pharmacology , Perylene/analogs & derivatives , Quinones/pharmacology , SARS-CoV-2/drug effects , Virus Internalization/drug effects , Naphthoquinones/chemistry , Perylene/chemistry , Perylene/pharmacology , Quinones/chemistry , SARS-CoV-2/physiology
Molecules ; 25(7)2020 Mar 27.
Article in English | MEDLINE | ID: covidwho-326826


Malaria is a life-threatening disease and, what is more, the resistance to available antimalarial drugs is a recurring problem. The resistance of Plasmodium falciparum malaria parasites to previous generations of medicines has undermined malaria control efforts and reversed gains in child survival. This paper describes a continuation of our ongoing efforts to investigate the effects against Plasmodium falciparum strains and human microvascular endothelial cells (HMEC-1) of a series of methoxy p-benzyl-substituted thiazinoquinones designed starting from a pointed antimalarial lead candidate. The data obtained from the newly tested compounds expanded the structure-activity relationships (SARs) of the thiazinoquinone scaffold, indicating that antiplasmodial activity is not affected by the inductive effect but rather by the resonance effect of the introduced group at the para position of the benzyl substituent. Indeed, the current survey was based on the evaluation of antiparasitic usefulness as well as the selectivity on mammalian cells of the tested p-benzyl-substituted thiazinoquinones, upgrading the knowledge about the active thiazinoquinone scaffold.

Antimalarials/pharmacology , Endothelial Cells/drug effects , Malaria/drug therapy , Plasmodium falciparum/drug effects , Quinones/chemistry , Quinones/pharmacology , Endothelial Cells/parasitology , Inhibitory Concentration 50 , Parasitic Sensitivity Tests , Quinones/chemical synthesis , Structure-Activity Relationship