Identification of immunomodulatory drugs that inhibit multiple inflammasomes and impair SARS-CoV-2 infection

Autor(es):Mostrar menos -

de Almeida, Leticia ; da Silva, Alexandre L. N. ; Rodrigues, Tamara S. ; Oliveira, Samuel ; Ishimoto, Adriene Y. ; Seribelli, Amanda A. ; Becerra, Amanda ; Andrade, Warrison A. ; Ataide, Marco A. ; Caetano, Camila C. S. ; de Sa, Keyla S. G. ; Pelisson, Natalia ; Martins, Ronaldo B. ; Souza, Juliano de Paula ; Arruda, Eurico ; Batah, Sabrina S. ; Castro, Ricardo ; Frantz, Fabiani G. ; Cunha, Fernando Q. ; Cunha, Thiago M. ; Fabro, Alexandre T. ; Cunha, Larissa D. ; Louzada-Junior, Paulo ; de Oliveira, Rene D. R. ; Zamboni, Dario S.

• Tipo de documento: Artigo Científico
• Fonte: SCIENCE ADVANCES; v. 8, n. 37, p. 15-pg., 2022-09-16.

Resumo

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces mild or asymptomatic COVID-19 in most cases, but some patients develop an excessive inflammatory process that can be fatal. As the NLRP3 inflammasome and additional inflammasomes are implicated in disease aggravation, drug repositioning to target inflammasomes emerges as a strategy to treat COVID-19. Here, we performed a high-throughput screening using a 2560 small-molecule compound library and identified FDA-approved drugs that function as pan-inflammasome inhibitors. Our best hit, niclosamide (NIC), effectively inhibits both inflammasome activation and SARS-CoV-2 replication. Mechanistically, induction of autophagy by NIC partially accounts for inhibition of NLRP3 and AIM2 inflammasomes, but NIC-mediated inhibition of NAIP/NLRC4 inflammasome are autophagy independent. NIC potently inhibited inflammasome activation in human monocytes infected in vitro, in PBMCs from patients with COVID-19, and in vivo in a mouse model of SARS-CoV-2 infection. This study provides relevant information regarding the immunomodulatory functions of this promising drug for COVID-19 treatment. (AU)

• Processo FAPESP: 20/04964-8 - Ativação do inflamassoma pelo SARS-CoV-2 e o papel dessa plataforma na patogênese do COVID-19: estudo prospectivo visando inibição de NLRP3 para tratamento da COVID-19
• Beneficiário: Dario Simões Zamboni
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 13/08216-2 - CPDI - Centro de Pesquisa em Doenças Inflamatórias
• Beneficiário: Fernando de Queiroz Cunha
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
• Processo FAPESP: 19/11342-6 - Mecanismos e consequências da ativação de receptores citoplasmáticos por patógenos intracelulares
• Beneficiário: Dario Simões Zamboni
• Modalidade de apoio: Auxílio à Pesquisa - Temático