RS-5645 attenuates inflammatory cytokine storm induced by SARS-CoV-2 spike protein and LPS by modulating pulmonary microbiota.

An inflammatory cytokine storm is considered an important cause of death in severely and critically ill COVID-19 patients, however, the relationship between the SARS-CoV-2 spike (S) protein and the host's inflammatory cytokine storm is not clear. Here, the qPCR results indicated that S protein induced a significantly elevated expression of multiple inflammatory factor mRNAs in peripheral blood mononuclear cells (PBMCs), whereas RS-5645 ((4-(thiophen-3-yl)-1-(p-tolyl)-1H-pyrrol-3-yl)(3,4,5-trimethoxyphenyl)methanone) attenuated the expression of the most inflammatory factor mRNAs. RS-5645 also significantly reduced the cellular ratios of CD45+/IFNγ+, CD3+/IFNγ+, CD11b+/IFNγ+, and CD56+/IFNγ+ in human PBMCs. In addition, RS-5645 effectively inhibited the activation of inflammatory cells and reduced inflammatory damage to lung tissue in mice. Sequencing results of 16S rRNA v3+v4 in mouse alveolar lavage fluid showed that there were 494 OTUs overlapping between the alveolar lavage fluid of mice that underwent S protein+ LPS-combined intervention (M) and RS-5645-treated mice (R), while R manifested 64 unique OTUs and M exhibited 610 unique OTUs. In the alveoli of group R mice, the relative abundances of microorganisms belonging to Porphyromonas, Rothia, Streptococcus, and Neisseria increased significantly, while the relative abundances of microorganisms belonging to Psychrobacter, Shimia, and Sporosarcina were significantly diminished. The results of KEGG analysis indicated that the alveolar microbiota of mice in the R group can increase translation and reduce the activity of amino acid metabolism pathways. COG analysis results indicated that the abundance of proteins involved in ribosomal structure and biogenesis related to metabolism was augmented in the alveolar microbiota of the mice in the R group, while the abundance of proteins involved in secondary metabolite biosynthesis was significantly reduced. Therefore, our research results showed that RS-5645 attenuated pulmonary inflammatory cell infiltration and the inflammatory storm induced by the S protein and LPS by modulating the pulmonary microbiota.

Targeting the Interaction between the SH3 Domain of Grb2 and Gab2.

Gab2 is a scaffolding protein, overexpressed in many types of cancers, that plays a key role in the formation of signaling complexes involved in cellular proliferation, migration, and differentiation. The interaction between Gab2 and the C-terminal SH3 domain of the protein Grb2 is crucial for the activation of the proliferation-signaling pathway Ras/Erk, thus representing a potential pharmacological target. In this study, we identified, by virtual screening, seven potential inhibitor molecules that were experimentally tested through kinetic and equilibrium binding experiments. One compound showed a remarkable effect in lowering the affinity of the C-SH3 domain for Gab2. This inhibitory effect was subsequently validated in cellula by using lung cancer cell lines A549 and H1299. Our results are discussed under the light of previous works on the C-SH3:Gab2 interaction.

Indolyl aryl sulfones as HIV-1 non-nucleoside reverse transcriptase inhibitors: role of two halogen atoms at the indole ring in developing new analogues with improved antiviral activity.

Indolyl aryl sulfones bearing the 4,5-difluoro (10) or 5-chloro-4-fluoro (16) substitution pattern at the indole ring were potent inhibitors of HIV-1 WT and the NNRTI-resistant strains Y181C and K103N-Y181C. These compounds were highly effective against the 112 and the AB1 strains in lymphocytes and inhibited at nanomolar concentration the multiplication of the IIIBBa-L strain in macrophages. Compound 16 was exceptionally potent against RT WT and RTs carrying the K103N, Y181I, and L100I mutations.