RESUMO
DNA-encoded chemical library (DEL) technology provides a time- and cost-efficient method to simultaneously screen billions of compounds for their affinity to a protein target of interest. Here we report its use to identify a novel chemical series of inhibitors of the thioesterase activity of polyketide synthase 13 (Pks13) from Mycobacterium tuberculosis (Mtb). We present three chemically distinct series of inhibitors along with their enzymatic and Mtb whole cell potency, the measure of on-target activity in cells, and the crystal structures of inhibitor-enzyme complexes illuminating their interactions with the active site of the enzyme. One of these inhibitors showed a favorable pharmacokinetic profile and demonstrated efficacy in an acute mouse model of tuberculosis (TB) infection. These findings and assay developments will aid in the advancement of TB drug discovery.
Assuntos
Antituberculosos , Inibidores Enzimáticos , Mycobacterium tuberculosis , Bibliotecas de Moléculas Pequenas , Mycobacterium tuberculosis/enzimologia , Mycobacterium tuberculosis/efeitos dos fármacos , Animais , Camundongos , Antituberculosos/farmacologia , Antituberculosos/química , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Tuberculose/tratamento farmacológico , Tuberculose/microbiologia , Policetídeo Sintases/metabolismo , Policetídeo Sintases/química , Policetídeo Sintases/genética , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Tioléster Hidrolases/antagonistas & inibidores , Tioléster Hidrolases/metabolismo , Tioléster Hidrolases/química , Tioléster Hidrolases/genética , Cristalografia por Raios X , Humanos , Modelos Animais de DoençasRESUMO
Dysregulation of IL17A drives numerous inflammatory and autoimmune disorders with inhibition of IL17A using antibodies proven as an effective treatment. Oral anti-IL17 therapies are an attractive alternative option, and several preclinical small molecule IL17 inhibitors have previously been described. Herein, we report the discovery of a novel class of small molecule IL17A inhibitors, identified via a DNA-encoded chemical library screen, and their subsequent optimization to provide in vivo efficacious inhibitors. These new protein-protein interaction (PPI) inhibitors bind in a previously undescribed mode in the IL17A protein with two copies binding symmetrically to the central cavities of the IL17A homodimer.
