RESUMO
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.
Assuntos
Antivirais , Inibidores de Protease de Coronavírus , Furanos , Antivirais/química , Antivirais/farmacologia , Lactamas , Peptídeo Hidrolases , Inibidores de Proteases/farmacologia , Inibidores de Proteases/química , SARS-CoV-2 , Furanos/química , Inibidores de Protease de Coronavírus/químicaRESUMO
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.
Assuntos
Antibacterianos/farmacologia , Compostos Heterocíclicos com 3 Anéis/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/química , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Inibidores da Topoisomerase II/química , Inibidores da Topoisomerase II/farmacologia , Animais , Antibacterianos/química , Antibacterianos/farmacocinética , Técnicas de Química Sintética , DNA Topoisomerases Tipo II/química , DNA Topoisomerases Tipo II/metabolismo , Cães , Avaliação Pré-Clínica de Medicamentos/métodos , Canal de Potássio ERG1/metabolismo , Bactérias Anaeróbias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Compostos Heterocíclicos com 3 Anéis/síntese química , Compostos Heterocíclicos com 3 Anéis/química , Infecções Pneumocócicas/tratamento farmacológico , Ratos , Infecções Respiratórias/tratamento farmacológico , Infecções Respiratórias/microbiologia , Inibidores da Topoisomerase II/farmacocinéticaRESUMO
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.
Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , DNA Girase/química , Quinolinas/química , Quinolinas/farmacologia , Staphylococcus aureus/enzimologia , Inibidores da Topoisomerase II , Antibacterianos/metabolismo , Apoenzimas/química , Apoenzimas/metabolismo , Arginina/metabolismo , Ácido Aspártico/metabolismo , Sítios de Ligação , Domínio Catalítico , Ciprofloxacina/química , Ciprofloxacina/metabolismo , Cristalografia por Raios X , DNA/química , DNA/metabolismo , Clivagem do DNA , DNA Girase/metabolismo , DNA Super-Helicoidal/química , DNA Super-Helicoidal/metabolismo , Desenho de Fármacos , Resistência a Medicamentos , Escherichia coli/enzimologia , Manganês/metabolismo , Modelos Moleculares , Conformação Proteica , Quinolinas/metabolismo , Quinolonas/química , Quinolonas/metabolismo , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Bactérias/enzimologia , Naftiridinas/química , Naftiridinas/farmacologia , Inibidores da Topoisomerase II/química , Inibidores da Topoisomerase II/farmacologia , Animais , Cristalografia por Raios X , Cães , Ativação Enzimática/efeitos dos fármacos , Haplorrinos , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , RatosRESUMO
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.
Assuntos
Acinetobacter baumannii/enzimologia , DNA Topoisomerase IV/química , Inibidores Enzimáticos/química , Quinolonas/química , DNA Topoisomerase IV/farmacologia , Inibidores Enzimáticos/farmacologia , Modelos Moleculares , Estrutura Quaternária de Proteína , Estrutura Terciária de Proteína , Quinolonas/farmacologiaRESUMO
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.