Pharmacological Reviews最新文献

Antimicrobial resistance represents one of the most pressing global health challenges of the 21st century, significantly compromising the efficacy of conventional antibiotics. In response to this crisis, the World Health Organization has updated its 2024 list of priority bacterial pathogens-classified into critical-, high-, and medium-risk groups-based on their resistance mechanisms, clinical impact, and global dissemination. This comprehensive review explores the emerging therapeutic potential of antimicrobial peptides (AMPs) when used in synergistic combinations with conventional antibiotics. By dissecting the mechanistic interplay-ranging from membrane disruption and efflux pump inhibition to biofilm penetration and intracellular antibiotic delivery-we provide a structured analysis of how these dual strategies overcome specific resistance barriers. Special emphasis is given to the World Health Organization-designated pathogens such as Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Staphylococcus aureus (methicillin-resistant/vancomycin-resistant), Enterococcus faecium, Salmonella spp., Shigella spp., and Mycobacterium tuberculosis. Supported by extensive in vitro and in vivo data, this review catalogs dozens of successful AMP-antibiotic pairings, highlighting their fractional inhibitory concentration indices, clinical relevance, and implications for translational development. The evidence presented demonstrates that AMPs not only potentiate antibiotic action but also extend the useful lifespan of existing drugs while reducing toxicity. These findings support the advancement of AMP-based combination therapies as a next-generation strategy to contain resistance and restore the effectiveness of the antimicrobial arsenal. SIGNIFICANCE STATEMENT: Antimicrobial resistance remains a global health emergency, especially among World Health Organization 2024 priority pathogens. This review highlights the therapeutic promise of synergistic combinations between antimicrobial peptides and conventional antibiotics, offering a rational strategy to restore efficacy, overcome resistance mechanisms, and extend the clinical utility of existing drugs. By bridging microbiology, pharmacology, and translational medicine, this work provides timely insights for researchers and policymakers seeking innovative solutions to combat multidrug-resistant infections.

Artificial intelligence (AI) has progressed from experimental curiosity to clinical utility, with AI-designed therapeutics now in human trials across diverse therapeutic areas. This review critically compares 5 leading AI-driven discovery platforms: generative chemistry, phenomics-first systems, integrated target-to-design pipelines, knowledge-graph repurposing, and physics-plus-machine learning design. Key developments since 2024 include positive phase IIa results for Insilico Medicine's Traf2- and Nck-interacting kinase inhibitor, ISM001-055, in idiopathic pulmonary fibrosis. Another key development was the Recursion-Exscientia merger, which integrated phenomic screening with automated precision chemistry into a full end-to-end platform. In addition, advancement of the Nimbus-originated tyrosine kinase 2 inhibitor, zasocitinib (TAK-279), into phase III clinical trials exemplifies Schrödinger's physics-enabled design strategy reaching late-stage clinical testing. Emerging platforms such as Insitro, Isomorphic Labs, Atomwise, and XtalPi illustrate the field's expanding geographic and technical footprint. SIGNIFICANCE STATEMENT: Artificial intelligence (AI) is reshaping pharmacology by shortening discovery timelines, potentially reducing attrition, and expanding the design space of therapeutic candidates. Alongside technical milestones, regulatory and ethical frameworks from the US Food and Drug Administration and European Medicines Agency are beginning to address transparency, bias, accountability, intellectual property, and data privacy. Robotics tightly integrated with AI now enables self-driving laboratories that accelerate design-make-test-learn cycles and improve reproducibility. Together, these advances chart a forward-looking roadmap in which multimodal foundation models, robotics-led platforms, and hybrid physics-AI strategies are poised to accelerate translation, derisk development, and establish trustworthy AI as a cornerstone of modern drug discovery.

In 2015, we coined the term "Resolution Pharmacology" to indicate how the biology of the resolution of inflammation could, and should, be harnessed to produce novel therapeutics. Here we update these concepts and discuss the most recent developments in this innovative field of pharmacology. We begin by discussing how the inflammatory response is lifesaving through the engagement, expression, and function of several mediators, which have been labeled as proinflammatory or proresolving mediators. In reality, they act in concert and regulate each other in a fully integrated fashion, so that the notion between inflammation onset and inflammation resolution, as 2 distinct phases, is mainly didactic and temporal. Moreover, the observation that the inflammatory reaction that our body mounts always, or nearly always, resolves indicate that inflammation resolution is a robust process. What remain to be addressed, though, is how to harness the biology of acute resolving inflammation so that innovative therapeutic options can be offered for the clinical management of chronic nonresolving inflammation. The holistic view of physiological inflammation, and its disruption in pathology, comes with implications in relation to the application of Resolution Pharmacology. We predict resolution-based drugs will work better in presence of a florid inflammatory status, which would augment expression of resolution targets. We conclude by proposing a renovated focus on endogenous tissue-protective regenerative pathways by specific targets for drug development programs: Resolution Pharmacology remains an untapped opportunity for the pharmaceutical industry. SIGNIFICANCE STATEMENT: The process of the resolution of inflammation represents an integral part of the whole acute inflammatory response. A florid inflammatory reaction ensures proper engagement of resolution mechanisms. Dysregulation in resolution mechanisms can lead to disease. Conversely, harnessing resolution can offer therapeutic guidance to develop medicines that are disease independent, broadening their potential. There is ongoing intensive clinical development in this area. Proresolving drugs will be patient centric in their pharmacology and would promote natural processes of healing and repair.

Transient receptor potential (TRP) channels represent an extensive and diverse protein family fulfilling salient roles as versatile cellular sensors and effectors. The pivotal role of TRP and related ion channels in sensory processes has been well documented. Over the last few years, a new concept has emerged that TRP proteins control an exceptionally broad spectrum of homeostatic physiological functions such as maintenance of body temperature, blood pressure, transmitter release from neurons, mineral and energy homeostasis, and reproduction. This notion is further supported by more than 20 hereditary human diseases in areas as diverse as neurology, cardiology, hematology, pulmonology, nephrology, dermatology, and urology. Most TRP channel-related human disorders impinge on development, metabolism, and other homeostatic functions. The remarkable diversity of pathologies caused by TRP channel dysfunction underscores these proteins' broad spectrum of roles in vivo. Here, we provide a comprehensive overview of our progress in the identification, characterization, and clinical relevance of pharmacological agents targeting mammalian TRP channels. SIGNIFICANCE STATEMENT: Accumulating evidence links transient receptor potential (TRP) channels to various human diseases and highlights TRPs as the most appealing pharmacological targets. The review provides an overview of this quickly developing research area, focusing on identified pharmacological modulators of mammalian TRP channels.

The extracellular accumulation of adenosine is a central mechanism of immune evasion within the tumor microenvironment. Elevated adenosine levels-driven by hypoxia, chronic inflammation, and upregulated ectonucleotidase activity, primarily through ectonucleoside triphophate diphosphoydrolase 1 and ecto-5'-nucleotidase-induce profound immunosuppression and promote tumor progression. In this setting, adenosine acts mainly through 2 G protein-coupled receptors, the adenosine A_2A receptor (A_2AAR) and the adenosine A_2B receptor (A_2BAR), which modulate diverse immune and stromal cell populations. A_2AAR signaling suppresses the effector activity of cytotoxic T lymphocytes and natural killer cells, whereas A_2BAR activation exerts broader effects by amplifying myeloid-derived immunosuppression, driving stromal remodeling, and fostering angiogenesis and metastatic dissemination. This review provides a comprehensive overview of the distinct and converging roles of A_2AAR and A_2BAR in immune, stromal, and tumor compartments. We critically analyze current strategies for developing selective and dual A_2AAR/A_2BAR antagonists, with a focus on structure-activity relationships, scaffold optimization, and pharmacokinetic profiling. In addition, we examine ongoing clinical trials and emerging combination therapies involving A_2AAR and A_2BAR antagonists in conjunction with immune checkpoint inhibitors, adoptive cell therapies, enzymatic axis blockade, radiotherapy, and classical chemotherapy. We also underscore the therapeutic potential of dual A_2AAR/A_2BAR antagonists as a multitarget approach to counteract overlapping immunosuppressive mechanisms. Overall, targeting the adenosine axis-particularly through dual receptor blockade-represents a promising strategy for reprograming the tumor microenvironment, reinvigorating antitumor immunity, and improving the efficacy of cancer immunotherapy. SIGNIFICANCE STATEMENT: Adenosine signaling via adenosine A_2A (A_2AAR) and A_2B (A_2BAR) receptors plays a central role in tumor-induced immunosuppression, limiting the efficacy of cancer immunotherapy. This review provides an integrated analysis of A_2AAR and A_2BAR functions across immune and stromal compartments, summarizes current selective antagonists (A_2AAR and A_2BAR) and dual antagonists, and highlights compounds in clinical studies. Moreover, it discusses synergistic combination strategies that integrate adenosine blockade with complementary immunotherapeutic and conventional approaches to enhance antitumor responses.

The endoplasmic reticulum (ER) is a dynamic membranous organelle that accounts for nearly half of the total membrane content in hepatocytes and serves as a central hub for protein folding and lipid biosynthesis. Given the liver's essential functions in protein production and secretion, lipid handling, and xenobiotic metabolism, hepatocyte ER homeostasis is essential for systemic metabolic control and health. Metabolic dysfunction-associated steatotic liver disease, which affects nearly 30% of the global population, is strongly linked to hepatic ER stress. Accumulating evidence highlights the unfolded protein response (UPR) as a key mechanistic regulator that integrates proteostasis and metabolic stress, thereby influencing disease progression from simple steatosis to inflammation-driven metabolic dysfunction-associated steatohepatitis (MASH). More recently, ER stress has also been implicated as a driver of MASH-related hepatocellular carcinoma, the most common primary liver cancer. In this review, we provide a comprehensive overview of the dynamic roles of the UPR and ER stress in hepatocytes, with particular emphasis on mechanistic insights derived from murine models of MASH-related hepatocellular carcinoma. We also summarize the current animal models of MASH that depend on hepatic ER stress. Finally, we discuss therapeutic candidates for MASH treatment, whose mechanisms of action involve ER stress and the UPR. SIGNIFICANCE STATEMENT: The endoplasmic reticulum (ER) functions as a central signaling hub, transmitting stress cues to transcriptional and translational programs through activation of the unfolded protein response, which orchestrates adaptive responses required for stress recovery. Given that hepatocytes are the largest cell population responsible for systemic protein distribution through ER-regulated protein synthesis, precise control of hepatic ER stress is essential not only for maintaining normal hepatocyte function but also for developing therapeutic strategies against ER stress-driven metabolic dysfunction-associated steatotic liver disease.

Before the Framingham Heart Study, the concept of cardiovascular disease (CVD) risk factors did not exist, and CVDs were seen as a consequence of aging. The first 2 reports in 1957 and 1961 identified high cholesterol levels as a major risk factor for CVD, highlighting the importance of lipid management to reduce CVD risk. Since then, the growing knowledge of CVD pathophysiology has led to the development of many drug classes to manage dyslipidemia and consequently, cardiovascular disease risk. Unfortunately, many of them, such as high-density lipoprotein-targeted or triglyceride-modulating drugs, have so far failed in clinical trials due to a lack of efficacy in cardiovascular disease protection or due to the appearance of side effects. Interestingly, low-density lipoprotein-targeted statin therapy revolutionized cardiovascular risk management and remains today the reference treatment in primary and secondary CVD prevention. In the last decades, novel low-density lipoprotein-targeted drugs, such as ezetimibe, proprotein convertase subtilisin/kexin type 9-targeted therapies, and bempedoic acid, have been approved by the Food and Drug Administration and have now found their place among the therapeutic arsenal of hypolipidemic drugs used in CVD risk management, in case of intolerance to statins or often in association with statins. This review focuses on the historical evolution of development strategies and on the successes and failures of lipid-lowering drugs to reduce cardiovascular disease risk, from the mid-20th century to the present, and concludes with novel challenging strategies in progress. SIGNIFICANCE STATEMENT: This review highlights the evolution of lipid-lowering therapies in atherosclerotic cardiovascular disease management, from statins to proprotein convertase subtilisin/kexin type 9 inhibitors. It underscores key successes, limitations, and emerging strategies, offering essential insights into their current and future roles in reducing atherosclerotic cardiovascular disease risk for a broad medical and scientific audience.

Globally, breast cancer (BC) remains the leading cause of cancer death in women. BC profoundly impacts the physical and psychological well being of millions of families worldwide and significantly burdens the healthcare system and the economy. Although chemotherapy remains a key component in BC treatment, its effectiveness is often limited by severe side effects and the development of drug resistance, highlighting the urgent need for innovative therapeutic strategies. One strategy to minimize side effects involves conjugating anticancer agents with tumor-targeting molecules such as antibodies, nanobodies, or peptides to enhance their selective delivery to cancer cells. The success of platinum-based drugs such as cisplatin and carboplatin has urged the exploration of other metal-based complexes as therapeutic agents for BC. Metals, including copper, zinc, and gold, are considered promising candidates for anticancer therapy because of their well established cytotoxic properties and relatively low cost. This review examines the use of metal-based agents conjugated to tumor-targeting molecules for the treatment of BC. Additionally, we propose a novel approach to conjugate innovative thiosemicarbazone-copper complexes with a targeting moiety, aiming to overcome 2 major clinical challenges of current anticancer drugs: side effects and drug resistance. SIGNIFICANCE STATEMENT: Metal-based drugs possess potent anticancer properties through diverse mechanisms. However, current agents like cisplatin face 2 major challenges common to most anticancer therapies: toxic side effects and drug resistance. One strategy to address these issues is the conjugation of anticancer agents to specific tumor-targeting moieties, such as antibodies, nanobodies, or peptides. To further limit resistance development, drug conjugates can be designed to include a potent, multitargeted payload, such as a thiosemicarbazone-copper complex that targets lysosomes.

Voltage-gated ion channels (VGICs) are critical regulators of membrane potential, cellular excitability, and calcium signaling in both excitable and nonexcitable tissues and constitute important drug targets for neurological, cardiovascular, and immunological diseases. This review describes recent progress in the pharmacology of voltage-gated Na⁺, voltage-gated Ca²⁺, and voltage-gated K⁺ channels, highlighting clinical-stage compounds, emerging therapeutic modalities, and new strategies in VGIC drug discovery, emphasizing the increasingly central role of protein structures and artificial intelligence. Several compounds targeting VGICs have progressed to clinical trials for epilepsy, atrial fibrillation, psoriasis, and difficult-to-treat disorders, such as chronic pain, schizophrenia, major depression, and amyotrophic lateral sclerosis. The therapeutic landscape for VGIC-related disorders is expanding beyond traditional small molecules and antisense oligonucleotides and gene therapies targeting VGICs at the mRNA or gene level are currently in both early and late clinical trial stages for Dravet syndrome and developmental epileptic encephalopathy. The progression of such varied modalities suggests that the extensive efforts dedicated to elucidating VGIC biophysics and structure, coupled with rigorous target validation, are beginning to translate into therapeutic advancements. Furthermore, we discuss emerging discovery strategies, including the growing impact of VGIC structures, computational structural modeling, virtual screening of focused and ultralarge libraries, and artificial intelligence-driven redesign and de novo design of biologics. Although these approaches are poised to substantially accelerate the early stages of ion channel drug discovery, the clinical stages will continue to require careful selection of indications and thoughtful clinical trial design to fully realize the long-held potential of VGICs as drug targets. SIGNIFICANCE STATEMENT: Drug development for voltage-gated ion channels is widely considered to be challenging. This article reviews recent advances in the pharmacology of voltage-gated Na⁺, voltage-gated Ca²⁺, and voltage-gated K⁺ channels by examining compounds currently in clinical trials, including emerging new therapeutic approaches such as antisense oligonucleotides and gene therapy. We then discuss noteworthy recent developments, including the increasing availability and impact of ion channel structures, structural modeling, virtual screening, and artificial intelligence-assisted protein design, which are likely to accelerate the early stages of ion channel drug discovery. Success of the later stages will continue to rely on rigorous target validation, and proper choices of clinical candidates and clinical trial design.

Evidence-based lipid-lowering therapies have significantly reduced, but not eradicated, atherosclerosis-induced cardiovascular disease, which remains a significant cause of morbidity and mortality around the world. This article focuses on precision medicine and examines the transformative potential of multiomics and machine learning in advancing theranostic approaches for atherosclerosis. The integration of multimodal data, known as multiomics, encompassing genomics and epigenomics, transcriptomics and epitranscriptomics, proteomics, metabolomics, and lipidomics, can support the comprehensive interrogation of molecular changes associated with disease initiation and progression. Machine learning algorithms are critical for identifying pertinent features of highly diverse and heterogeneous multiomic datasets. The combination of these new laboratory and data science technologies offers unprecedented opportunities for increasing precision in disease prediction, early detection, and monitoring, as well as more personalized treatments with current and new drugs. This article discusses the implications. It discusses their importance in the development and adoption of personalized medicine based on therapeutic approaches. SIGNIFICANCE STATEMENT: The review article explores new opportunities to develop and adopt theranostic strategies for atherosclerosis, derived from the integration of multiomics and machine learning to enhance personalized pharmacotherapy, precision prognostics, and diagnostics of atherosclerosis and atherosclerosis-derived cardiovascular diseases.