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.
Blockade of the interaction between programmed cell death ligand-1 (PD-L1) and its receptor PD-1 has shown great success in cancer immunotherapy. Peptides possess unique characteristics that give them significant advantages as immune checkpoint inhibitors. However, unfavorable physicochemical properties and proteolytic stability profiles limit the translation of bioactive peptides as therapeutic agents. Studies have revealed that cyclization improves the biological activity and stability of linear peptides. In this study, we report the use of macrocyclization scanning for the discovery of cyclic anti-PD-L1 peptides with improved bioactivity. The cyclic peptides demonstrated up to a 34-fold improvement in the PD-1/PD-L1 blocking activity and significant in vivo anti-tumor activity. Our results demonstrate that macrocyclization scanning is an effective way to improve the serum stability and bioactivity of the anti-PD-L1 linear peptide. This strategy can be employed in the optimization of other bioactive peptides, particularly those for protein–protein interaction modulation.
Liver fibrosis is the excessive accumulation of extracellular matrix (ECM) in the liver due to chronic injuries and inflammation. These injuries activate and transform quiescent hepatic stellate cells (HSCs) into proliferative myofibroblast-like cells, which are the key contributors to the secretin of ECM in the fibrotic liver. The insulin-like growth factor 2 receptor (IGF2R) is a multifunctional receptor that is overexpressed on activated HSCs and is a specific molecular marker of activated HSCs in the fibrotic liver. We recently discovered an IGF2R-specific peptide that significantly increases the binding affinity and uptake of a protein-based siRNA nanocomplex to activated HSCs. However, there is a potential concern about the immunogenicity of protein-based siRNA delivery systems. In this study, we used the IGF2R-specific peptide to modify a small peptide-based siRNA nanocomplex for HSC-specific drug delivery. We incorporated a short spacer and glutamate residues into the IGF2R peptides. The siRNA nanocomplex modified with the IGF2R-3GK6E peptide demonstrated higher HSC specificity compared to an unmodified nanocomplex. This peptide-based nanocomplex provides a promising platform to effectively deliver Pcbp2 siRNA to activated HSCs for the treatment of liver fibrosis.
Lymphocyte activation gene-3 (LAG-3) has emerged as a promising target for cancer immunotherapy. It is expressed on activated CD4+ and CD8+ T cells, and on the surface of B cells, natural killer cells, and dendritic cells (DC). It has also been found to be highly expressed on activated T cells upon treatment with monoclonal antibodies targeting the PD-1/PD-L1 pathway, which may explain the resistance mechanism of monotherapy. Several anti-LAG-3 antibodies are being examined in clinical trials to treat different types of cancers. Despite their specificity and affinity, antibody-based checkpoint inhibitors are hampered by poor tumor permeability and high production costs. In this study, we aimed to discover a small peptide-based anti-LAG-3 inhibitor using a novel biopanning technique developed in our laboratory. We discovered several anti-LAG-3 inhibitor peptides, and the CMA16 peptide showed the highest stability and blocking efficacy. The peptides were synthesized by the solid-phase peptide synthesis using PurePepTM Chorus synthesizer (Gyros Protein Technologies, Tucson, AZ). The molecular weights and purity were confirmed by mass spectrometry and HPLC, respectively. To evaluate the function of the CMA16 peptide, a series of in vitro functional assays including binding ELISA, serum stability and cell viability assays were performed. In vivo anti-tumor activity of the peptides was examined in five-week-old C57BL/6 mice bearing MC38 cells. CMA16 significantly inhibited the growth of MC38 tumors. Quantification of CD8+ tumor-infiltrating cells revealed a significant increase in this type of immune cells in the group of mice treated with CMA16. These findings support the further development of the CMA16 peptide as potential anti-LAG-3 inhibitor for cancer immunotherapy. Citation Format: Mohammed Alahmari, Umar-Farouk Mamani, Yuhan Guo, Chien-Yu Lin, Mohammed Nurudeen Ibrahim, Yongren Li, Kun Cheng. A small molecular-weight anti-lag-3 peptide inhibits colon tumor growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB194.
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