Identification of immunomodulatory drugs that inhibit multiple inflammasomes and impair SARS-CoV-2 infection
Letícia de Almeida, Alexandre L. N. da Silva, Tamara Silva Rodrigues, Samuel Oliveira, Adriene Y. Ishimoto, Amanda Aparecida Seribelli, Amanda Becerra, Warrison A. Andrade, Marco A. Ataide, Camila Carla da Silva Caetano, Keyla Santos Guedes de Sá, Natália Pelisson, Ronaldo B. Martins, Juliano de Paula Souza, Eurico Arruda, Sabrina Setembre Batah, Ricardo Cardoso Castro, Fabiani Gai Frantz, Fernando Q. Cunha, Thiago M. Cunha, Alexandre Todorovic Fabro, Larissa D. Cunha, Paulo Louzada‐Júnior, Renê Donizeti Ribeiro de Oliveira, Dario S. Zamboni
Abstract
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.