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The outbreak of pneumonia caused by a new coronavirus (SARS-CoV-2) occurred in December 2019, and spread rapidly throughout the world. There have been other severe coronavirus outbreaks worldwide, namely, severe acute respiratory syndrome (SARS-CoV) and Middle East respiratory syndrome (MERS-CoV). Because the genetic diversity of coronaviruses renders the design of vaccines complicated, broad spectrum-anti-coronavirus drugs have become a critical approach to control the coronavirus epidemic. Cyclophilin A is an important protein needed for coronavirus replication, and its inhibitor cyclosporine A has the ability to suppress coronavirus on a broad spectrum. CD147-S protein was found to be one route by which SARS-CoV-2 invades host cells, while CD147 was found to play a functional role in facilitating the infection of host cells by SARS-CoV. The CyPA/CD147 interaction may play a critical role in the ability of the SARS-CoV-2 virus to enter the host cells. However, cyclosporine A has immunosuppressive effects, so the conditions for its use as an antiviral drug are limited. As a result, cyclosporine A analogues without immunosuppressive side effects have attracted lots of interest. This review primarily discusses the drug development prospects of cyclophilin A as a therapeutic target for the treatment of coronavirus infection, especially coronavirus disease 2019 (COVID-19), and non-immunosuppressive cyclosporine analogues.

The overall response rate for anti-PD-1 therapy remains modest in hepatocellular carcinoma (HCC). We found that a combination of interferon alpha (IFN-a) and anti-PD-1-based immunotherapy resulted in enhanced antitumor activity in unresectable HCC patients. In both immunocompetent orthotopic and spontaneous HCC models, IFN-a therapy synergized with anti-PD-1 and the combination treatment led to significant enrichment of cytotoxic CD27+ CD8+ T cells. Mechanistically, IFN-a suppressed HIF1a signaling by inhibiting FosB transcription in HCC cells, resulting in reduced glucose consumption capacity and consequentially establishing the high-glucose microenvironment that fostered transcription of the T cell costimulatory molecule Cd27 via mTOR-FOXM1 signaling in infiltrating CD8+ T cells. Together, these data reveal that IFN-a reprograms glucose metabolism within HCC tumor microenvironment, thereby liberating T cell cytotoxic capacities and potentiating the PD-1 blockade-induced immune response. Our findings suggest that IFN-a and anti-PD-1 cotreatment is an effective novel combination strategy for HCC patients.

To date, the overall response rate of PD-1 blockade remains unsatisfactory, partially due to limited understanding of tumor immune microenvironment (TIME). B-cell lymphoma 9 (BCL9), a key transcription co-activator of the Wnt pathway, is highly expressed in cancers. By genetic depletion and pharmacological inhibition of BCL9 in tumors, we found that BCL9 suppression reduced tumor growth, promoted CD8+ T cell tumor infiltration, and enhanced response to anti-PD-1 treatment in mouse colon cancer models. To determine the underlying mechanism of BCL9’s role in TIME regulation, single-cell RNA-seq was applied to reveal cellular landscape and transcription differences in the tumor immune microenvironment upon BCL9 inhibition. CD155-CD226 and CD155-CD96 checkpoints play key roles in cancer cell/CD8+ T cell interaction. BCL9 suppression induces phosphorylation of VAV1 in CD8+ T cells and increases GLI1 and PATCH expression to promote CD155 expression in cancer cells. In The Cancer Genome Atlas database analysis, we found that BCL9 expression is positively associated with CD155 and negatively associated with CD226 expression. BCL9 is also linked to adenomatous polyposis coli (APC) mutation involved in patient survival following anti-PD-1 treatment. This study points to cellular diversity within the tumor immune microenvironment affected by BCL9 inhibition and provides new insights into the role of BCL9 in regulating CD226 and CD96 checkpoints

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Background and purpose PD‐1/PD‐L1 antibodies have achieved great success in clinical treatment. However, monoclonal antibody drugs also have challenges, such as high manufacturing costs, poor diffusion, low oral bioavailability and limited penetration into tumour tissue. The development of small‐molecule inhibitors of PD‐1/PD‐L1 interaction represents a promising perspective to overcome the above challenges in cancer immunotherapy. Experimental approach We explored structural activity relationships and used biochemical assays to generate a lead compound (ZE132). CD8+ T‐cells killing assay and Ifng expression assay were used to verify the in vitro cellular activity of ZE132. Off‐target study was performed to verify the selectivity. Syngeneic mouse models were used to verify the in vivo activity of ZE132 in tumour immune microenvironment (TIME). We also performed pharmacokinetics profiling in mice and The Cancer Genome Atlas database analysis. Key results ZE132 can effectively inhibit the PD‐1/PD‐L1 interactions in vitro, and it has a potent affinity to PD‐L1. ZE132 shows robust anti‐tumour effects in vivo, better than anti‐PD‐1 antibody. In the analysis of TIME, we found that ZE132 treatment promotes cytotoxic T‐cell tumour infiltration and induces IL‐2 expression. In addition, ZE132 elicits strong inhibitory effects on the mRNA expression of TGF‐β, which may serve as a potential biomarker to predict responsiveness to PD‐1/PD‐L1 immunotherapies. Conclusion and implications We identified a new lead compound ZE132 targeting PD‐1/PD‐L1 interactions, not only showing favourable drug‐like properties in vitro and in vivo but also showing the advantage of overcoming the barrier of TIME compared to anti‐PD‐1 antibody.

Wnt/β-catenin signaling is crucial both in normal embryonic development and throughout the life of an organism. Moreover, aberrant Wnt signaling has been associated with various diseases, especially cancer and fibrosis. Recent research suggests that direct targeting of the β-catenin/BCL9 protein–protein interaction (PPI) is a promising strategy to block the Wnt pathway. Progress in understanding the cocrystalline complex and mechanism of action of the β-catenin/BCL9 interaction facilitates the discovery process of its inhibitors, but only a few inhibitors have been reported. In this review, the discovery and development of β-catenin/BCL9 PPI inhibitors in the areas of drug design, structure–activity relationships and biological and biochemical properties are summarized. In addition, perspectives for the future development of β-catenin/BCL9 PPI inhibitors are explored.

Dysregulation of the Wnt/β-catenin signaling pathway is strongly associated with various aspects of cancer, including tumor initiation, proliferation, and metastasis as well as antitumor immunity, and presents a promising opportunity for cancer therapy. Wnt/β-catenin signaling activation increases nuclear dephosphorylated β-catenin levels, resulting in β-catenin binding to TCF and additional cotranscription factors, such as BCL9, CBP, and p300. Therefore, directly disrupting β-catenin’s interactions with these nuclear partners holds promise for the effective and selective suppression of the aberrant activation of Wnt/β-catenin signaling. Herein, we summarize recent advances in biochemical techniques and medicinal chemistry strategies used to identify potent peptide-based and small-molecule inhibitors that directly disrupt β-catenin’s interactions with its nuclear binding partners. We discuss the challenges involved in developing drug-like inhibitors that target the interactions of β-catenin and its nuclear binding partner into therapeutic agents.