Ali Jahanian-Najafabadi

Purpose The immune system combats viral infections through innate and adaptive responses, with macrophages and dendritic cells playing key roles in pathogen clearance. Neutralizing antibodies aid viral elimination but have variable efficacy against SARS-CoV-2, which uses ACE2 for entry. Human recombinant soluble ACE2 (hrsACE2) acts as a decoy to block viral entry but has limitations in affinity and immune uptake. We produced mannosylated hrsACE2 (Mann-hrsACE2) via a baculovirus expression system to enhance uptake by innate immune cells, aiming to improve viral neutralization and stimulate cell-mediated immunity against SARS-CoV-2. Methods Mann-hrsACE2 protein was produced in Sf9 insect cells using recombinant baculovirus, purified by Ni–NTA chromatography, and verified by SDS-PAGE and Western blot. Its interaction with macrophages was assessed by FITC-labeling and analyzed through fluorescence microscopy and flow cytometry. Results Expressed Mann-hrsACE2 displayed an upward shift SDS-PAGE and Western blot analysis. Flow cytometry revealed macrophage uptake of Mann-hrsACE2 at 3, 28, and 98% corresponding to concentrations of 1, 10, and 51 nM, respectively. Conclusion The increased molecular weight of the expressed protein confirmed its glycosylation. Its mannosylation enabled efficient uptake by macrophages, key antigen-presenting cells in the immune system. Furthermore, by binding to SARS-CoV-2, the protein not only inhibits viral entry but also redirects the virus to macrophages for enhanced immune clearance.

Lasso peptides, a significant group of ribosomally synthesized and post-translationally modified peptides (RiPPs), have emerged as potential therapeutic agents owing to their unique structural features and diverse biological activities. These peptides are characterized by an isopeptide-bonded macrolactam ring and a tail threaded through the ring, forming a distinctive lasso structure that provides remarkable stability and functionality, leading to significant therapeutic potential for antimicrobial, antiviral, anticancer, and anti-inflammatory applications. This review highlights the structural diversity and therapeutic applications of lasso peptides, emphasizing their potential as next-generation therapeutics. Additionally, while their mechanisms of action and innovative therapeutic prospects are explored, the challenges and limitations associated with their use are also discussed.

Despite great advances in cancer identification and treatment, malignancies remain the primary cause of high morbidity and mortality worldwide. The drawbacks of conventional chemotherapy, such as severe toxicity, lack of specificity related to actively dividing cells, and resistance, can warrant the urgent need to develop an alternative approach to treat this disease. To overcome the drawbacks, researchers are attempting to deliver drugs to the site of action (targeted delivery) or to identify drugs that specifically target tumor cells. In this regard, highly cationic and amphipathic antimicrobial peptides are attracting the attention of researchers due to their potent anticancer activity, low cost of manufacture, and, most critically, tumor-targeting activity. A growing number of documents have shown that some of the mentioned peptides exhibited a broad spectrum of cytotoxic activity against cancer cells but not normal mammalian cells entitled as anticancer peptides. Due to their solubility, low toxicity, strong tumor penetration, high selectivity, and ability to be used alone or in conjunction with other conventional medications, anticancer peptides have the potential to become very successful cancer treatments in the future. This review provided an overview of the studies concerning anticancer peptide classification, modes of action, and selectivity, and also summarized some of the anticancer peptides developed for targeting different types of malignancies. The role of in silico methods or artificial intelligence in the design and discovery of anticancer peptides was briefly explained. Additionally, the current review addressed challenges in utilizing anticancer peptides for cancer therapy and highlighted peptides currently undergoing clinical trials.

Cancer is one of the prominent causes of death worldwide. Despite the existence of various modalities for cancer treatment, many types of cancer remain uncured or develop resistance to therapeutic strategies. Furthermore, almost all chemotherapeutics cause a range of side effects because they affect normal cells in addition to malignant cells. Therefore, the development of novel therapeutic agents that are targeted specifically toward cancer cells is indispensable. Immunotoxins (ITs) are a class of tumor cell-targeted fusion proteins consisting of both a targeting moiety and a toxic moiety. The targeting moiety is usually an antibody/antibody fragment or a ligand of the immune system that can bind an antigen or receptor that is only expressed or overexpressed by cancer cells but not normal cells. The toxic moiety is usually a protein toxin (or derivative) of animal, plant, insect, or bacterial origin. To date, three ITs have gained Food and Drug Administration (FDA) approval for human use, including denileukin diftitox (FDA approval: 1999), tagraxofusp (FDA approval: 2018), and moxetumomab pasudotox (FDA approval: 2018). All of these ITs take advantage of bacterial protein toxins. The toxic moiety of the first two ITs is a truncated form of diphtheria toxin, and the third is a derivative of Pseudomonas exotoxin (PE). There is a growing list of ITs using PE, or its derivatives, being evaluated preclinically or clinically. Here, we will review these ITs to highlight the advances in PE-based anticancer strategies, as well as review the targeting moieties that are used to reduce the non-specific destruction of non-cancerous cells. Although we tried to be as comprehensive as possible, we have limited our review to those ITs that have proceeded to clinical trials and are still under active clinical evaluation.