Medicinal Research Reviews最新文献

β-Adrenoceptors are important G protein-coupled receptors involved in cardiovascular, metabolic, and neurological regulation. To study their function with high precision, light-based molecular tools have been developed offering precise spatiotemporal control. Fluorescence and bioluminescence techniques allow real-time monitoring of receptor activation and organization, while photopharmacology and optogenetics enable precise external modulation of their activity. A particularly valuable approach involves photoswitchable ligands, which can be switched on and off by specific wavelengths and provide reversible control over receptor activity. In general, the combination of optical biosensing and photopharmacology enhances our ability to analyze GPCR signaling dynamics and function with minimal perturbation. In particular, these approaches open new avenues for targeted research and therapeutic interventions, offering a powerful framework for understanding β-adrenoceptors-related diseases.

The rat sarcoma virus oncogene (RAS) is one of the most frequently mutated drivers in human cancers. Developing targeted therapies against RAS has been challenging due to its structure. The recent breakthroughs with covalent Kirsten RAS (KRAS) inhibitors represent a key milestone in targeting mutant KRAS proteins. However, drug resistance remains a significant obstacle. The proteolysis-targeting chimeras (PROTACs), which degrade mutant KRAS proteins, offer a promising strategy to overcome resistance and expand therapeutic options. This review covers the structural basis of KRAS and signaling networks, while discussing recent advancements in KRAS inhibitor research and PROTAC technology. It aims to provide a foundation and inspiration for future KRAS inhibitor and degrader development.

Tuberculosis (TB) is one of the most significant health perils that has claimed more lives than any other contagious disease over the past 2000 years. The treatment of tuberculosis has been severely compromised due to drug-resistant strains. In this review, we cover the field of the clinical pipeline of tuberculosis drugs, and summarize the progress of their targets and structures. A wide range of marine natural products (MNPs) with novel structures and remarkable activities have potential for the development of antituberculosis drugs. We systematically summarize the progress and potential of 107 potent MNPs that have shown activity against tuberculosis infection. Additionally, we highlight the physicochemical properties of MNPs, total synthesis, and biosynthesis of bioactive compounds, to further evaluate their drug-likeness and sustainability of compound supply. However, the intricate nature of the pathogen, drug misuse, bottlenecks in the supply of MNPs, and other problems pose challenges to reaching the goal of completely eradicating tuberculosis worldwide. Reliable alternative models, screening based on enzyme activity, and combination therapies may be transforming discovery and application in the field of antituberculosis drugs, accelerating discovery and improving sustainable therapeutic effects. These promising lead compounds and widely emerging technologies broaden horizons for developing marine drugs.

CD73, a membrane-bound ecto-5'-nucleotidase, catalyzes the extracellular conversion of adenosine monophosphate into immunosuppressive adenosine. Functioning as an emerging immune checkpoint, CD73 is frequently upregulated across numerous tumor types, contributing to the accumulation of adenosine within the tumor microenvironment and promoting immune evasion. Intensive efforts have led to the discovery of diverse CD73 inhibitors, which show strong potential in cancer immunotherapy. To date, around eighteen candidates targeting CD73 have entered clinical evaluation, many exhibiting encouraging efficacy in combination regimens for solid tumors. This review provides an overview of the biological functions of CD73 in tumor-induced immunosuppression and highlights the medicinal chemistry strategies employed in the development of small-molecule CD73 inhibitors since 2018. Additionally, the challenges in drug design and future directions are also discussed to enhance the clinical applicability of CD73-targeted therapies in cancer treatment. We believe that this review will offer valuable insights to guide the rational design of next-generation CD73 inhibitors for cancer immunotherapy.

The cover image is based on the article Covalent Bifunctional Molecules (CBMs): Achievements and Challenges by Yuting Xin et al., https://doi.org/10.1002/med.70011.

Since 2013, a rapidly expanding portfolio of U.S. Food and Drug Administration (FDA)-approved drugs has highlighted pyrimidine as one of the most versatile and therapeutically valuable heteroaromatic scaffolds. Building on more than six decades of medicinal chemistry, these recent approvals underscore the pivotal role of pyrimidines in modern drug discovery across oncology, anti-infectives, immunology, immuno-oncology, neurological disorders, chronic pain, and metabolic diseases. This review systematically surveys pyrimidine-containing drugs approved from 2013 to the present, detailing their synthetic strategies, key biological targets, and disease-specific mechanisms of action. This review demonstrates the enduring value of pyrimidine as a privileged chemotype and bioisostere for phenyl and other aromatic π-systems, offering insights to guide the design of next-generation therapeutics for conditions once considered intractable.

Respiratory syncytial virus (RSV) is a common virus that causes respiratory infections, posing a serious threat, particularly to infants, the elderly, and individuals with compromised immune systems. As the leading cause of lower respiratory tract infections (LRTIs) in infants, RSV is responsible for millions of cases worldwide each year. Its incidence rises significantly during the winter influenza season. Despite decades of research, no effective vaccine exists, and antiviral treatment options remain limited, presenting a major challenge to global public health. With the advancement of emerging technologies, researchers have made significant progress in understanding the pathological and biological characteristics of RSV, the mechanisms of immune response, and its long-term health impacts. This review aims to provide a comprehensive overview of the basic biological characteristics, epidemiology, clinical manifestations, and diagnostic and therapeutic strategies of RSV and to explore preventive measures and future research directions, offering the latest scientific evidence for RSV prevention and control.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by inflammation of the joint synovium, which can lead to bone destruction. Prolonged inadequate treatment can result in joint disability and an increased risk of mortality. Currently, there are considerable limitations in the availability of effective therapeutic agents for RA. The IL-23/IL-17/NF-κB signaling pathway has emerged as a central pathogenic mechanism underlying the multistage development of RA. This pathway initiates the initial inflammatory response, driving excessive proliferation of the synovial tissue, ultimately leading to late-stage bone and cartilage destruction. A comprehensive understanding of the role of the IL-23/IL-17/NF-κB pathway in the pathogenesis of RA can facilitate the refinement of scientific understanding of RA pathogenesis and assist in developing new therapeutic regimens. A comprehensive literature review and data search were conducted in several scientific databases, including Web of Science, PubMed, Google Scholar, Embase, TCMSP, PubChem, Swiss ADME, and Swiss Target Prediction. The literature review was conducted from 2013 to 2025. The search terms employed included RA, IL-23, IL-17, NF-κB, molecular mechanisms, and therapeutic agents. Following a rigorous screening process, irrelevant data were excluded, resulting in a focused analysis and comprehensive review of the key role of the IL-23/IL-17/NF-κB signaling axis in the multifaceted pathogenesis of RA and the key active ingredients and possible targets of action of related drugs. This comprehensive literature review aims to provide novel mechanistic insights and valuable references to guide the development of more effective therapeutic strategies for this debilitating autoimmune disease.

Cancer is the second leading cause of death globally, with an estimated worldwide incidence of 19.3 million cases in 2020, and is expected to increase by 47% in the next 20 years. Painful symptoms of tumors and anticancer treatment negatively impact the quality of life of patients with cancer. Cancer pain can occur during all disease periods, being more debilitating and hardest to treat, mainly when tumors metastasize to the bone. Common tumors such as breast, lung, and prostate often metastasize to the bones and cause severe pain in patients. Anticancer therapy with some chemotherapy and hormonal drugs also induces painful symptoms, compromising antineoplastic treatment. Among the analgesics recommended to treat cancer pain, NSAIDs and paracetamol seem to have predominantly antiproliferative activity. However, opioids, mainly morphine, present conflicting effects in reducing and promoting tumor progression. Kinins and their B₁ and B₂ receptors contribute to the development of numerous painful symptoms,including those induced by tumors and anticancer therapy. In addition, kinins stimulate the proliferation of various tumors (breast, lung, prostate and others) while having controversial effects in melanoma. Thus, kinin B₁ and B₂ receptors could be a promising pharmacological target to treat the pain caused by the tumor and its therapy while reducing tumor proliferation. However, it is essential to review the effects of kinins in each specific type of cancer to investigate their involvement in pain. This assessment is also valid and prudent for new analgesic candidates against cancer pain and their therapy, especially to rule out a possible pro-tumor activity of this analgesic.

Benzodiazepine drugs (BZDs) have been central to neuropsychopharmacology since the 1960s, acting as positive allosteric modulators of γ-aminobutyric acid type A (GABA_A) receptors to enhance inhibitory neurotransmission. Despite their clinical efficacy, long-term use is limited by tolerance, dependence, and cognitive side effects. This review summarizes the structural evolution of BZD modulators, with a focus on subtype-selective interactions with GABA_A receptor isoforms. Advances in cryo-electron microscopy and AI-driven modeling have clarified the architecture and pharmacological roles of distinct receptor subunits, enabling the design of ligands that dissociate therapeutic effects from adverse outcomes. We also highlight the development of nonclassical scaffolds-such as imidazopyridines, triazolopyridazines, and cinnolines-which improve metabolic stability and subtype specificity. In addition, emerging formulation technologies and novel indications, including chronic pain, asthma, and neurodegenerative disorders, broaden the therapeutic scope of BZD-related compounds. Collectively, these advances underscore a shift toward rational, structure-based design of next-generation BZD receptor modulators with improved efficacy, safety, and clinical precision.