The spike protein is a focused target of COVID-19, a pandemic caused by SARS-CoV-2. A 12-nt insertion at S1/S2 in the spike coding sequence yields a furin cleavage site, which raised controversy views on origin of the virus. Here we analyzed the phylogenetic relationships of coronavirus spike proteins and mapped furin recognition motif on the tree. Furin cleavage sites occurred independently for multiple times in the evolution of the coronavirus family, supporting the natural occurring hypothesis of SARS-CoV-2.

Adrenergic receptors are G protein-coupled receptors for epinephrine and norepinephrine. They are targets of many drugs for various conditions, including treatment of hypertension, hypotension, and asthma. Adrenergic receptors are intensively studied in structural biology, displayed for binding poses of different types of ligands. Here, we summarized molecular mechanisms of ligand recognition and receptor activation exhibited by structure. We also reviewed recent advances in structure-based ligand discovery against adrenergic receptors.

Litter size is an economically important trait in sheep breeding. The objectives of this study were as follows: (1) to ascertain if any of the 19 known variants in the BMPRIB, BMP15, and GDF9 genes are present and associated with the litter size of Mongolia sheep; (2) to identify novel variants in GDF9 and perform association analysis; and (3) to validate the effects of these GDF9 promoter variants on the activity of the gene. The results of the 19 known variants showed that the FecB^B affected the litter size of Mongolia sheep (p < 0.001). The association analysis results of novel variants showed that the g.46544883A>G (GenBank accession: NC_040256, the same below) in the 3’ untranslated region (3’ UTR), the c.1040T>C (Phe347Ser) in the exon 2, and the g.46547859C>T SNP in the promotor of GDF9 were significantly associated with litter size of Mongolia ewes (p < 0.01, p < 0.05, and p < 0.001, respectively). In addition, the GDF9 promoter activity analysis showed that the C allele at the −332 position (g.46547859C>T) could decrease luciferase activity compared with the T allele (p < 0.01). Our findings may facilitate effective marker-assisted selection to increase litter size in Mongolia sheep populations, as well as bring new insights into GDF9 expression.

Aberrant activation of EGFR drives the progression of non-small-cell lung cancer (NSCLC). As one of the most prevalent driver genes in NSCLC, EGFR represents a critical therapeutic target for patients with NSCLC. In this study, we synthesized 2,4-pyrimidinediamine derivative ZX-3. Compared to its lead compound ceritinib, which has weak cytotoxicity for EGFR-driven NSCLC, ZX-3 exhibited potent cytotoxicity against EGFR-driven NSCLC. We further investigated the antitumor activity and mechanisms of ZX-3 both in vitro and in vivo. Through high-throughput target screening using RTK protein arrays and surface plasmon resonance (SPR) assays, it was demonstrated that ZX-3 reversibly targets the EGFR protein and inhibits its downstream PI3K/AKT signaling pathway. In vitro experiments revealed that ZX-3 suppresses cell colony formation in H2228 cells, induces G1-phase cell cycle arrest, and promotes apoptosis. In in vivo xenograft studies, ZX-3 treatment significantly suppressed tumor growth without obvious toxicity. Collectively, ZX-3 represents a reversible EGFR inhibitor based on borylation modification and possesses favorable antitumor activity both in vitro and in vivo, offering a novel strategy for the subsequent development of EGFR-targeted inhibitors.