Medicinal Research Reviews最新文献

The active sites of numerous metalloproteins feature two metal ion cofactors—either identical or distinct—that are positioned in close proximity, typically around 3.8 Å apart. This two-metal-ion catalytic mechanism (TCM) endows these enzymes with a remarkable catalytic efficiency. Enzymes employing TCM play vital biological roles in both humans and pathogenic organisms, with some identified as validated therapeutic targets. Various rational drug design approaches, including nucleoside analogs, prodrugs, metal-binding group design, bioisosteres, pharmacophore modeling, scaffold hopping, tautomerism, and structure-based drug design, have been successfully applied to several enzymes with TCMs, thus yielding the development and approval of many small-molecule drugs for the treatment of several diseases, including certain catastrophic illnesses, such as hepatitis C infection, coronavirus disease 2019, and acquired immune deficiency syndrome. Additionally, drug repurposing has proven to be a critical strategy in the development of therapeutics targeting TCM enzymes. This article reviews the significant achievements in design and development of small-molecule drugs targeting several enzymes with TCMs, including RNA-dependent RNA polymerase, HIV-1 integrase, influenza virus cap-dependent endonuclease, and phosphodiesterase, hoping to offer valuable insights and guidance to facilitate future drug discovery efforts focused on these enzymes and related molecular targets.

Jellyfish are vital components of marine ecosystems and significantly impact human life and industry. Globally, jellyfish populations are increasing annually, but their applications are currently limited primarily to food processing. Jellyfish contain various peptides and proteins that humans can utilize because of their unique biological structures and compositions. In particular, jellyfish are rich in bioactive peptides that intrigue researchers. Jellyfish bioactive peptides can be categorized functionally into toxin peptides, neuropeptides, antioxidant peptides, angiotensin-converting enzyme (ACE) inhibitory peptides, and antimicrobial peptides (AMPs), each with distinct physiological roles, such as inflammation, apoptosis, ion pathway, reproduction, and vision. They are demonstrated to have valuable pharmacological potential against various diseases, including neurodegenerative disorders, wound healing, osteoarthritis and cancer, and are candidate for nutraceuticals. This review primarily summarizes the reported bioactive peptides from jellyfish, improving our understanding of their potential pharmacological effects and nutraceutical activities, which may promote the further utilization and development of bioactive peptides from jellyfish.

High Mobility Group Box 1 (HMGB1) is a nuclear protein crucial for nucleosome stability, gene regulation, DNA repair, cell differentiation, and development. Extracellularly, HMGB1 functions as a cytokine, significantly impacting inflammation, immune response, and the pathogenesis of various diseases, including cancer and inflammatory disorders. Research highlights HMGB1's complex role in cancer, where it promotes tumorigenesis through chronic inflammation and immune suppression while enhancing chemotherapy and genome stability. It also influences cell proliferation, angiogenesis, metastasis, and chemotherapy resistance. In inflammatory diseases, HMGB1 has a dual role: it can promote inflammation in conditions like ischemia-reperfusion injury and sepsis but also induces immune tolerance and suppression. This review provides a comprehensive overview of HMGB1's structure, functions, and regulatory mechanisms, discussing recent advances in understanding its roles in cancer and inflammatory diseases. We emphasize the evolving therapeutic strategies targeting HMGB1, underscoring its potential as a promising target for treating both cancer and inflammatory disorders.

Arginine is critical in biosynthesis, energy generation, cell proliferation, and immune regulation. In the tumor microenvironment (TME), due to limited supply and high consumption, the competition for arginine is extremely fierce. It always ends up with the victory of tumor cells and immunosuppressive cells, which leads to the arginine deficiency for anti-tumor immune cells, resulting in immune tolerance of tumors. Therapies based on arginine metabolism have been extensively studied. An arginine deprivation therapy has been developed as the tumor progression relies on arginine support. To reverse the arginine shortage of anti-tumor immune cells in TME, supplying arginine to enhance immune therapy has been proposed. Achieving the optimal antitumor effects of these two opposed therapies requires a better understanding of arginine metabolism in TME. In this review, we compared the transport, synthesis, and metabolism of arginine in tumor cells and various immune cells, and proposed key processes that may serve as potential therapeutic targets. In addition, for the two therapies for arginine, deprivation and supplementation, the recent research of them was discussed, and the relevant clinical trials were collected and summarized, which might provide reliable references for the further study and application of arginine-based therapies.

Antimicrobial peptides (AMPs), essential components of the body's innate defense system, are expected to exert and enhance their potential antimicrobials, immunomodation and other bio-activities that combine with traditional antimicrobial agents and vaccines efficiently against multi-drug-resistant (MDR) bacteria. They are multi-source (animal, plant, microbial, etc.) and multi-functional (antimicrobial, immunomodulatory, anticancer, antiviral, antioxidant, etc.), and have been clearly categorized according to source, function, and structure in several AMP databases. However, there is insufficient evidence to support recognizing, developing, and utilizing the source–function relationship of AMPs, as their first function is usually unknown or unclear; in addition, they are usually accompanied by some shortcomings such as weak stability, high toxicity, and production cost. These have seriously hindered their development for clinical application. Therefore, it is necessary to clarify the relationship between the AMP source and function, and establish a complete system to distinguish the first function, so that more AMP candidates can enter the pipeline of new drugs as early as possible. At the same time, the key fundamental elements, scaffold and bottom logistics were proposed for the R & D pipeline of AMPs as new antimicrobial agents, including the following key points: high yielding, stability, and safety of AMPs using heterologous expression, modification, encapsulation, and coadministration toward their final successful application.

Pulmonary arterial hypertension (PAH) is a rare and life-threatening pulmonary vascular disease distinguished by vasoconstriction and remodeling of the pulmonary artery, leading to sustained elevated pulmonary artery pressure, right ventricular failure, and even death. Receptor tyrosine kinases (RTKs) are critical in PAH pathogenesis, and targeted therapies against RTKs are becoming a research hotspot due to their potential to inhibit cell proliferation and right ventricular hypertrophy. Abnormal activation of RTKs induces downstream signaling cascades, including metabolic reprogramming through multiple regulatory crosstalk, to meet high energy requirements during cell proliferation. However, the crucial connection between metabolic reprogramming and RTKs in PAH remains largely unexplored. In this review, we focus on four key RTKs: Platelet-Derived Growth Factor Receptor (PDGFR), Epidermal Growth Factor Receptor (EGFR), Fibroblast Growth Factor Receptor (FGFR), and Vascular Endothelial Growth Factor Receptor (VEGFR) in the metabolic reprogramming of PAH and explore hypotheses that require further validation. The aim is to highlight how these mechanisms can be applied to develop better therapeutic strategies.