ABSTRACT
The virally encoded 3C-like protease (3CLpro) is a well-validated drug target for the inhibition of coronaviruses including Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). Most inhibitors of 3CLpro are peptidomimetic, with a γ-lactam in place of Gln at the P1 position of the pseudopeptide chain. An effort was pursued to identify a viable alternative to the γ-lactam P1 mimetic which would improve physicochemical properties while retaining affinity for the target. Discovery of a 2-tetrahydrofuran as a suitable P1 replacement that is a potent enzymatic inhibitor of 3CLpro in SARS-CoV-2 virus is described herein.
Subject(s)
Antiviral Agents , Coronavirus Protease Inhibitors , Furans , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Lactams , Peptide Hydrolases , Protease Inhibitors/pharmacology , Protease Inhibitors/chemistry , SARS-CoV-2 , Furans/chemistry , Coronavirus Protease Inhibitors/chemistryABSTRACT
During the course of our research on the lead optimisation of the NBTI (Novel Bacterial Type II Topoisomerase Inhibitors) class of antibacterials, we discovered a series of tricyclic compounds that showed good Gram-positive and Gram-negative potency. Herein we will discuss the various subunits that were investigated in this series and report advanced studies on compound 1 (GSK945237) which demonstrates good PK and in vivo efficacy properties.
Subject(s)
Anti-Bacterial Agents/pharmacology , Heterocyclic Compounds, 3-Ring/pharmacology , Heterocyclic Compounds, 4 or More Rings/chemistry , Heterocyclic Compounds, 4 or More Rings/pharmacology , Topoisomerase II Inhibitors/chemistry , Topoisomerase II Inhibitors/pharmacology , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacokinetics , Chemistry Techniques, Synthetic , DNA Topoisomerases, Type II/chemistry , DNA Topoisomerases, Type II/metabolism , Dogs , Drug Evaluation, Preclinical/methods , ERG1 Potassium Channel/metabolism , Gram-Negative Anaerobic Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Heterocyclic Compounds, 3-Ring/chemical synthesis , Heterocyclic Compounds, 3-Ring/chemistry , Pneumococcal Infections/drug therapy , Rats , Respiratory Tract Infections/drug therapy , Respiratory Tract Infections/microbiology , Topoisomerase II Inhibitors/pharmacokineticsABSTRACT
Despite the success of genomics in identifying new essential bacterial genes, there is a lack of sustainable leads in antibacterial drug discovery to address increasing multidrug resistance. Type IIA topoisomerases cleave and religate DNA to regulate DNA topology and are a major class of antibacterial and anticancer drug targets, yet there is no well developed structural basis for understanding drug action. Here we report the 2.1 A crystal structure of a potent, new class, broad-spectrum antibacterial agent in complex with Staphylococcus aureus DNA gyrase and DNA, showing a new mode of inhibition that circumvents fluoroquinolone resistance in this clinically important drug target. The inhibitor 'bridges' the DNA and a transient non-catalytic pocket on the two-fold axis at the GyrA dimer interface, and is close to the active sites and fluoroquinolone binding sites. In the inhibitor complex the active site seems poised to cleave the DNA, with a single metal ion observed between the TOPRIM (topoisomerase/primase) domain and the scissile phosphate. This work provides new insights into the mechanism of topoisomerase action and a platform for structure-based drug design of a new class of antibacterial agents against a clinically proven, but conformationally flexible, enzyme class.
Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , DNA Gyrase/chemistry , Quinolines/chemistry , Quinolines/pharmacology , Staphylococcus aureus/enzymology , Topoisomerase II Inhibitors , Anti-Bacterial Agents/metabolism , Apoenzymes/chemistry , Apoenzymes/metabolism , Arginine/metabolism , Aspartic Acid/metabolism , Binding Sites , Catalytic Domain , Ciprofloxacin/chemistry , Ciprofloxacin/metabolism , Crystallography, X-Ray , DNA/chemistry , DNA/metabolism , DNA Cleavage , DNA Gyrase/metabolism , DNA, Superhelical/chemistry , DNA, Superhelical/metabolism , Drug Design , Drug Resistance , Escherichia coli/enzymology , Manganese/metabolism , Models, Molecular , Protein Conformation , Quinolines/metabolism , Quinolones/chemistry , Quinolones/metabolism , Structure-Activity RelationshipABSTRACT
During the course of our research to find novel mode of action antibacterials, we discovered a series of hydroxyl tricyclic compounds that showed good potency against Gram-positive and Gram-negative pathogens. These compounds inhibit bacterial type IIA topoisomerases. Herein we will discuss structure-activity relationships in this series and report advanced studies on compound 1 (GSK966587) which demonstrates good PK and in vivo efficacy properties. X-ray crystallographic studies were used to provide insight into the structural basis for the difference in antibacterial potency between enantiomers.
Subject(s)
Bacteria/enzymology , Naphthyridines/chemistry , Naphthyridines/pharmacology , Topoisomerase II Inhibitors/chemistry , Topoisomerase II Inhibitors/pharmacology , Animals , Crystallography, X-Ray , Dogs , Enzyme Activation/drug effects , Haplorhini , Humans , Microbial Sensitivity Tests , Molecular Structure , RatsABSTRACT
Quinolone antibacterials have been used to treat bacterial infections for over 40 years. A crystal structure of moxifloxacin in complex with Acinetobacter baumannii topoisomerase IV now shows the wedge-shaped quinolone stacking between base pairs at the DNA cleavage site and binding conserved residues in the DNA cleavage domain through chelation of a noncatalytic magnesium ion. This provides a molecular basis for the quinolone inhibition mechanism, resistance mutations and invariant quinolone antibacterial structural features.
Subject(s)
Acinetobacter baumannii/enzymology , DNA Topoisomerase IV/chemistry , Enzyme Inhibitors/chemistry , Quinolones/chemistry , DNA Topoisomerase IV/pharmacology , Enzyme Inhibitors/pharmacology , Models, Molecular , Protein Structure, Quaternary , Protein Structure, Tertiary , Quinolones/pharmacologyABSTRACT
The design of conformationally restricted eight-membered ring diketones as transition state mimics of the mechanism of action of cyclotheonamides on serine proteases is described. Two target compounds are prepared from mutilin, derived from the natural product pleuromutilin. Compound 3 shows significant inhibition of plasmin and urokinase in enzyme rate assays, but an analogue 4 in which the amide moiety has been omitted does not. An X-ray crystal structure of the diketone 3 confirms the conformational predictions made by molecular modelling.