Identification of P218 as a potent inhibitor of Mycobacterium ulcerans DHFR

Autor(es)

Riboldi, Gustavo P. ^{[1, 2]} ; Zigweid, Rachael ^[3] ; Myler, Peter J. ^{[3, 4]} ; Mayclin, Stephen J. ^{[5, 6]} ; Counago, Rafael M. ^{[1, 2]} ; Staker, Bart L. ^[3]

Afiliação do(s) autor(es)

^[1] Univ Estadual Campinas, Dept Genet & Evolucao, Inst Biol, Struct Genom Consortium, BR-13083886 Campinas, SP - Brazil

^[2] Univ Estadual Campinas, UNICAMP, Ctr Biol Mol & Engn Genet CBMEG, Ctr Quim Med CQMED, BR-13083875 Campinas, SP - Brazil

^[3] Seattle Childrens Res Inst, Ctr Infect Dis Res, Seattle, WA 98109 - USA

^[4] Univ Washington, Dept Pediat, Seattle, WA 91895 - USA

^[5] Seattle Struct Genom Ctr Infect Dis SSGCID, Seattle, WA 98109 - USA

^[6] UCB, Bainbridge Isl, WA 98110 - USA

• Tipo de documento: Artigo Científico
• Fonte: RSC MEDICINAL CHEMISTRY; v. 12, n. 1, p. 103-109, JAN 1 2021.
• Citações Web of Science: 0

Resumo

Mycobacterium ulcerans is the causative agent of Buruli ulcer, a debilitating chronic disease that mainly affects the skin. Current treatments for Buruli ulcer are efficacious, but rely on the use of antibiotics with severe side effects. The enzyme dihydrofolate reductase (DHFR) plays a critical role in the de novo biosynthesis of folate species and is a validated target for several antimicrobials. Here we describe the biochemical and structural characterization of M. ulcerans DHFR and identified P218, a safe antifolate compound in clinical evaluation for malaria, as a potent inhibitor of this enzyme. We expect our results to advance M. ulcerans DHFR as a target for future structure-based drug discovery campaigns. (AU)

• Processo FAPESP: 13/50724-5 - Centro de Biologia Química de Proteínas Quinases: alavancando desenvolvimento de fármacos através de pesquisa de acesso aberto
• Beneficiário: Paulo Arruda
• Modalidade de apoio: Auxílio à Pesquisa - Parceria para Inovação Tecnológica - PITE
• Processo FAPESP: 14/50897-0 - INCT 2014: Centro de Química Medicinal de Acesso Aberto
• Beneficiário: Katlin Brauer Massirer
• Modalidade de apoio: Auxílio à Pesquisa - Temático