Diminazene aceturate inhibits the SARS-CoV-2 spike protein-induced inflammation involving leukocyte migration and DNA extracellular traps formation

• DOI: 10.1016/j.lfs.2024.122895
• Publication Date: 2024-07-08T17:45:11Z
• Authors: Gean C. Pereira-S...; Cassia K.C.A. Cor...; Gabriella Pacheco; Natalia C. Rochael; Isaac A.B. Gomes; Aurilene G. Cajado; Katriane C. Silva; Barbara Simonson ...; Jairo R. Temerozo; Ruan S. Bastos; Jefferson A. Rocha; Leonardo P. Souza; Marcellus H.L.P. ...; Roberto C.P. Lima...; Jand V.R. Medeiros; Marcelo C. Filgue...; Dumith Chequer Bo...; Elvira M. Saraiva; Lucas A.D. Nicolau

To investigate the SARS-CoV-2 Spike protein (Spk)-induced inflammatory response and its downmodulation by diminazene aceturate (DIZE).Through inducing Spk inflammation in murine models, leukocyte migration to the peritoneum, levels of myeloperoxidase (MPO), malondialdehyde (MDA), rolling and adhesion of mesenteric leukocytes, and vascular permeability were investigated. Extracellular DNA traps (DETs) induced by Spk and the production of IL-6 and TNF-α were analyzed using human neutrophils, monocytes, and macrophages. In silico assays assessed the molecular interaction between DIZE and molecules related to leukocyte migration and DETs induction.Spk triggered acute inflammation, demonstrated by increasing leukocyte migration. Oxidative stress was evidenced by elevated levels of MPO and MDA in the peritoneal liquid. DIZE attenuated cell migration, rolling, and leukocyte adhesion, improved vascular barrier function, mitigated DETs, and reduced the production of Spk-induced pro-inflammatory cytokines. Computational studies supported our findings, showing the molecular interaction of DIZE with targets such as β2 integrin, PI3K, and PAD2 due to its intermolecular coupling.Our results outline a novel role of DIZE as a potential therapeutic agent for mitigating Spk-induced inflammation.