The emergence of SARS‐CoV‐2 variants is a significant concern in developing effective therapeutics and vaccines in the middle of the ongoing COVID‐19 pandemic. Here, we have identified a novel small molecule that inhibited the interactions between SARS‐CoV‐2 spike RBDs and ACE2 by modulating ACE2 without impairing its enzymatic activity necessary for normal physiological functions. Furthermore, the identified compounds suppressed viral infection in cultured cells by inhibiting the entry of ancestral and variant SARS‐CoV‐2. Our study suggests that targeting ACE2 could be a novel therapeutic strategy to inhibit SARS‐CoV‐2 entry into host cells and prevent the development of COVID‐19.

Elucidation of the molecular mechanism of therapeutic agents and potential candidates is in high demand. Interestingly, rhenium-based complexes have shown a highly selective anticancer effect, only on cancer cells, unlike platinum-based drugs, such as cisplatin and carboplatin. These differences might be attributed to their different molecular targets. We confirmed that the target of tricarbonyl rhenium isonitrile polypyridyl (TRIP) complex is a protein, not DNA, using ICP-MS analysis and identified heat shock protein 60 (HSP60) as its target protein using a label-free target identification method. The subsequent biological evaluation revealed that TRIP directly inhibits the chaperone function of HSP60 and induces the accumulation of misfolded proteins in mitochondria, thereby leading to the activation of mitochondrial unfolded protein response (mtUPR)-mediated JNK2/AP-1/CHOP apoptotic pathway.

The emergence of SARS‐CoV‐2 variants is a significant concern in developing effective therapeutics and vaccines in the middle of the ongoing COVID‐19 pandemic. Here, we have identified a novel small molecule that inhibited the interactions between SARS‐CoV‐2 spike RBDs and ACE2 by modulating ACE2 without impairing its enzymatic activity necessary for normal physiological functions. Furthermore, the identified compounds suppressed viral infection in cultured cells by inhibiting the entry of ancestral and variant SARS‐CoV‐2. Our study suggests that targeting ACE2 could be a novel therapeutic strategy to inhibit SARS‐CoV‐2 entry into host cells and prevent the development of COVID‐19.

α-Galactosylceramide (α-GalCer) is a typical antigen for invariant natural killer T cells that are a subset of T cells and play critical roles in regulating immune responses. To selectively induce the secretion of certain cytokines via introducing hydrogen-bonding interaction with polar amino acid residues in the binding pocket of CD1d, a series of α-GalCer analogues with diether moiety in the acyl chain were designed and synthesized. The subsequent in vitro biological evaluation of these analogues revealed the structure−activity relationship for the selective IL-17 secretion. Analogues 5 and 6 induced the significantly increased IL-17 secretion over other cytokines, suggesting protective effects against pathogens. In contrast, analogue 7 showed the highly reduced IL-17 secretion, which may indicate potential anti-inflammatory effects.

Modulating target proteins via the ubiquitin‐proteasome system has recently expanded the scope of pharmacological inventions. Stimulator of interferon genes (STING) is an auspicious target for immunotherapy. Seminal studies envisioned the importance of STING as well as the utility of its agonists in immunotherapy outcomes. Herein, we suggest UPPRIS (upregulation of target proteins by protein‐protein interaction strategy) to pharmacologically increase cellular STING levels for improved immunotherapy. We discovered the small molecule SB24011 that inhibits STING‐TRIM29 E3 ligase interaction, thus blocking TRIM29‐induced degradation of STING. SB24011 enhanced STING immunity by upregulating STING protein levels, which robustly potentiated the immunotherapy efficacy of STING agonist and anti‐PD‐1 antibody via systemic anticancer immunity. Overall, we demonstrated that targeted protein upregulation of STING can be a promising approach for immuno‐oncology.