BackgroundImmunotherapy using checkpoint inhibitors, especially PD-1/PD-L1 inhibitors, has now evolved into the most promising therapy for cancer patients. However, most of these inhibitors are monoclonal antibodies, and their large size may limit their tumor penetration, leading to suboptimal efficacy. As a result, there has been a growing interest in developing low-molecular-weight checkpoint inhibitors.MethodsWe developed a novel biopanning strategy to discover small peptide-based anti-PD-L1 inhibitors. The affinity and specificity of the peptides to PD-L1 were examined using various assays. Three-dimensional (3D) spheroid penetration study was performed to determine the tumor penetration capability of the peptides. Anti-tumor activity of the peptides was evaluated in mice bearing CT26 tumor cells.ResultsWe discover several anti-PD-L1 peptide inhibitors to block PD-1/PD-L1 interaction. The peptides exhibit high affinity and specificity to human PD-L1 protein as well as PD-L1-overexpressing human cancer cells MDA-MB-231 and DU-145. Molecular docking studies indicate that the peptide CLP002 specifically binds to PD-L1 at the residues where PD-L1 interacts with PD-1. The peptide also blocks the CD80/PD-L1 interaction, which may further enhance the immune response of tumor-infiltrating T cells. Compared to antibody, the peptide CLP002 exhibits better tumor penetration in a 3D tumor spheroid model. The peptide CLP002 restores proliferation and prevents apoptosis of T cells that are co-cultured with cancer cells. The peptide CLP002 also inhibits tumor growth and increases survival of CT26 tumor-bearing mice.ConclusionsThis study demonstrated the feasibility of using phage display to discover small peptide-based checkpoint inhibitors. Our results also suggested that the anti-PD-L1 peptide represents a promising low-molecular-weight checkpoint inhibitor for cancer immunotherapy.Electronic supplementary materialThe online version of this article (10.1186/s40425-019-0705-y) contains supplementary material, which is available to authorized users.

Desmoplasia plays a pivotal role in promoting pancreatic cancer progression and is associated with poor clinical outcome. Targeting the desmoplastic tumor microenvironment in combination with chemotherapy is therefore a promising strategy for pancreatic cancer therapy. Here, we report a novel biodegradable copolymer to codeliver LY2109761 (a TGF-β receptor I/II inhibitor) and CPI-613 (a novel chemotherapy agent) to desmoplastic stroma and tumor cells, respectively, in the tumor microenvironment. Hydrophobic CPI-613 is conjugated to the hydrophilic copolymer via a newly designed MMP-2-responsive linker to form a trigger-responsive nanopolyplex. LY2109761 is hydrophobic and encapsulated into the hydrophobic core of the nanopolyplex. The resulting nanopolyplex is modified with a plectin-1-targeting peptide to enhance the accumulation of the nanopolyplex in pancreatic tumors. The nanopolyplex aims to normalize the stroma by blocking the interaction between tumor cells and pancreatic stellate cells to inhibit the activation of pancreatic stellate cells and subsequently reduce the dense extracellular matrix. Normalized stroma increases the penetration of the nanopolyplex into the tumor. The nanopolyplex shows enhanced accumulation in xenograft pancreatic tumors in a biodistribution study. Moreover, the targeted nanopolyplex markedly inhibits tumor growth in an orthotopic pancreatic cancer mouse model by dual-targeting tumor cells and stroma. Overall, the multifunctional nanopolyplex is a promising platform for pancreatic cancer therapy.

Ethnopharmacological Relevance: Xylopia aethiopica or Ethiopian pepper is a plant that thrives in most of the evergreen rain forests of tropical and subtropical Africa, and it is currently grown most prominently in Ghana as a crop. Almost all parts of Xylopia aethiopica possess great medicinal values in traditional medicine. In most parts of Africa, it is used in the treatment of cough, rheumatism, dysentery, malaria, uterine fibroid, boils, and wounds among others. This review summarizes published data on phytochemistry, toxicological properties, Ethnopharmacological and other uses of Xylopia aethiopica, and aims at providing an up-to-date detail that should constitute baseline information for future research on the plant. Materials and Methods: Google Scholar, Scifinder® and PubMed were the electronic databases used to search for and filter published research on Xylopia aethiopica. Results: The various parts of Xylopia aethiopica possess a wide diversity of phytochemicals. A detailed description of only a few of these phytochemicals i.e. essential oils, alkaloids and

COVID‐19 is caused by the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), which infects host cells by binding its viral spike protein receptor‐binding domain (RBD) to the angiotensin converting enzyme 2 (ACE2) on host cells. Blocking the SARS‐CoV‐2‐RBD/ACE2 interaction is, therefore, a potential strategy to inhibit viral infections. Using a novel biopanning strategy, a small anti‐ACE2 peptide is discovered, which shows high affinity and specificity to human ACE2. It blocks not only the SARS‐CoV‐2‐RBD/ACE2 interaction but also the SARS‐CoV‐1‐RBD/ACE2 interaction. Moreover, it inhibits SARS‐CoV‐2 infection in Vero‐E6 cells. The peptide shows negligible cytotoxicity in Vero‐E6 cells and Huh7 cells. In vivo short‐term lung toxicity study also demonstrates a good safety of the peptide after intratracheal administration. The anti‐ACE2 peptide can be potentially used as a prophylactic or therapeutic agent for SARS‐CoV‐2 or other ACE2‐mediated viruses. The strategy used in this study also provides a fast‐track platform to discover other antiviral peptides, which will prepare the world for future pandemics.

Liver fibrosis is a wound healing process marked by excessive accumulation of extracellular matrix in the liver. A poly(rC)-binding protein 2 (PCBP2) siRNA that reverses fibrogenesis in activated hepatic stellate cells (HSCs) has been recently discovered. However, targeted delivery of siRNAs to HSCs still remains a daunting challenge. Herein, a new strategy is developed to fabricate a multicomponent nanocomplex using siRNA/peptide nucleic acid (PNA) hybrid instead of chemically conjugated siRNA, thus increasing the scalability and feasibility of the siRNA nanocomplex for animal studies. The nanocomplex is modified with an insulin growth factor 2 receptor -specific peptide, which specifically binds to activated HSCs. The siRNA nanocomplex demonstrates a controllable size, high serum stability, and high cellular uptake in activated HSCs in vitro and in vivo. Anti-fibrotic activity of the siRNA nanocomplex is evaluated in rats with carbon tetrachloride-induced liver fibrosis. Treatment with the PCBP2 siRNA nanocomplex significantly inhibits the mRNA expressions of PCBP2 and type I collagen in fibrotic liver. The histology study reveals that the siRNA nanocomplex efficiently reduces the protein level of type I collagen and reverses liver fibrosis. The data suggests that the nanocomplex efficiently delivers the siRNA to fibrotic liver and produces a potent anti-fibrotic effect.