A MCL-1-targeted photosensitizer to combat triple-negative breast cancer with enhanced photodynamic efficacy, sensitization to ROS-induced damage, and immune response.

As growth factor receptor-2 (HER-2), progesterone receptor (PR) and estrogen receptor (ER) are scarce in triple-negative breast cancer (TNBC), it is a great challenge to combat TNBC with high tumor specificity and therapeutic efficacy. Most traditional treatments including surgical resection, chemotherapy, and radiotherapy would more or less cause serious side effects and drug resistance. Photodynamic therapy (PDT) has huge potential in the treatment of TNBC for minimal invasiveness, low toxicity, less drug resistance and high spatiotemporal selectivity. Inspired by the advantages of small-molecule-targeted PDT and the sensitization effect of myeloid cell leukemia-1 (MCL-1) inhibitor, a novel photosensitizer BC-Pc was designed by conjugating MCL-1 inhibitor with zinc phthalocyanines. Owning to 3-chloro-6-methyl-1-benzothiophene-2-carboxylic acid (BC) moiety, BC-Pc exhibits the high affinity towards MCL-1 and reduce its self-aggregation in TNBC cells. Therefore, MCL-1 targeted BC-Pc showed remarkable intracellular fluorescence and ROS generation in TNBC cells. Additionally, BC-Pc can selectively sensitize TNBC cells to ROS-induced damage, resulting in improved therapeutic effect to TNBC cells and negligible toxicity to normal cells. More importantly, BC-Pc can effectively inhibit the migration and invasion of TNBC cells, and enhance immune response, all of which will be beneficial to eradicate TNBC. To the best of our knowledge, BC-Pc is the novel MCL-targeted photosensitizer, which owns the amplified ROS-induced lethality and anticancer immune response for TNBC. Overall, our study provides a promising strategy to achieve targeting and highly efficient therapy of TNBC.

Punicalagin as an allosteric NSP13 helicase inhibitor potently suppresses SARS-CoV-2 replication in vitro.

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) helicase NSP13 plays a conserved role in the replication of coronaviruses and has been identified as an ideal target for the development of antiviral drugs against SARS-CoV-2. Here, we identify a novel NSP13 helicase inhibitor punicalagin (PUG) through high-throughput screening. Surface plasmon resonance (SPR)-based analysis and molecular docking calculation reveal that PUG directly binds NSP13 on the interface of domains 1A and 2A, with a KD value of 21.6 nM. Further biochemical and structural analyses suggest that PUG inhibits NSP13 on ATP hydrolysis and prevents it binding to DNA substrates. Finally, the antiviral studies show that PUG effectively suppresses the SARS-CoV-2 replication in A549-ACE2 and Vero cells, with EC50 values of 347 nM and 196 nM, respectively. Our work demonstrates the potential application of PUG in the treatment of coronavirus disease 2019 (COVID-19) and identifies an allosteric inhibition mechanism for future drug design targeting the viral helicases.

Discovery of a novel Aurora B inhibitor GSK650394 with potent anticancer and anti-aspergillus fumigatus dual efficacies in vitro.

Invasive fungal infections including Candidiasis and Aspergillosis are associated with considerable morbidity and mortality in immunocompromised individuals, such as cancer patients. Aurora B is a key mitotic kinase required for the cell division of eukaryotes from fungus to man. Here, we identified a novel Aurora B inhibitor GSK650394 that can inhibit the recombinant Aurora B from human and Aspergillus fumigatus, with IC50 values of 5.68 and 1.29 µM, respectively. In HeLa and HepG2 cells, GSK650394 diminishes the endogenous Aurora B activity and causes cell cycle arrest in G2/M phase. Further cell-based assays demonstrate that GSK650394 efficiently suppresses the proliferation of both cancer cells and Aspergillus fumigatus. Finally, the molecular docking calculation and site-directed mutagenesis analyses reveal the molecular mechanism of Aurora B inhibition by GSK650394. Our work is expected to provide new insight into the combinational therapy of cancer and Aspergillus fumigatus infection.

The search for inhibitors of macrodomains for targeting the readers and erasers of mono-ADP-ribosylation.

Macrodomains are evolutionarily conserved structural elements. Many macrodomains feature as binding modules of ADP-ribose, thus participating in the recognition and removal of mono- and poly-ADP-ribosylation. Macrodomains are involved in the regulation of a variety of physiological processes and represent valuable therapeutic targets. Moreover, as part of the nonstructural proteins of certain viruses, macrodomains are also pivotal for viral replication and pathogenesis. Thus, targeting viral macrodomains with inhibitors is considered to be a promising antiviral intervention. In this review, we summarize our current understanding of human and viral macrodomains that are related to mono-ADP-ribosylation, with emphasis on the search for inhibitors. The advances summarized here will be helpful for the design of macrodomain-specific agents for therapeutic and diagnostic applications.