Expert Opinion on Therapeutic Targets最新文献

Introduction: Indole-3-propionic acid (IPA), a tryptophan catabolite derived from gut bacterial metabolism, has been identified as a functional link between the gut microbiome and tuberculosis.

Area covered: IPA has gained ample attention over the past two decades on account of its multiple physiological roles, besides being both detectable and quantifiable. IPA is well studied across different health conditions, including cardiovascular and neurological conditions. IPA blocks tryptophan synthesis in Mycobacterium by binding to the allosteric tryptophan-binding site of TrpE, thereby threatening Mycobacterium survival due to tryptophan deficit.

Expert opinion: Characterizing IPA would enable its use as a tool to investigate the pathophysiology of tuberculosis. Integrating 'OMICS' techniques (through next-generation sequencing) along with targeted microbial metabolomics may help explore the possible association of serum IPA levels with TB in patients. This will aid in identifying IPA-producing gut microbes and selecting probiotic strains as a microbiome-targeting adjunct therapy, eventually enhancing our understanding of the molecular dynamics of the pathophysiology of tuberculosis in the context of the microbiome.

Introduction: Spinal and Bulbar Muscular Atrophy (SBMA) is a slowly progressive, X-linked, and sex-limited degenerative disorder affecting lower motor neurons and skeletal muscle which lacks disease-modifying therapies. This disease is caused by a CAG/polyglutamine (polyQ) tract expansion in the androgen receptor (AR) gene, and its pathogenesis is driven by toxic gain-of-function mechanisms. Affected men develop proximal limb and bulbar muscle weakness along with signs of partial androgen insensitivity.

Areas covered: Toxicity of the polyQ AR is mediated by protein misfolding and nuclear translocation that follow ligand binding, resulting in the disruption of downstream homeostatic mechanisms. This review highlights what is known about disease pathogenesis and how this has been leveraged to test potential therapeutic approaches. The focus is on strategies that alleviate polyQ AR toxicity in SBMA, including those that alter AR function, diminish the expression of the encoding gene, or promote clearance of the misfolded, mutant protein.

Expert opinion: We discuss emerging strategies to mitigate polyQ AR toxicity, including gene editing, RNA targeted therapies, and efforts to harness proteostatic mechanisms. These promising approaches are discussed in the context of challenges for drug discovery efforts that are faced when attempting to treat a rare and slowly progressive neurodegenerative disorder.

Introduction: Cardiovascular disease (CVD) is the leading cause of death worldwide. Platelet-derived extracellular vesicles (PEV) have attracted extensive attention in cardiovascular disease research in recent years because their cargo is involved in a variety of pathophysiological processes, such as thrombosis, immune response, promotion or inhibition of inflammatory response, promotion of angiogenesis as well as cell proliferation and migration.

Areas covered: This review explores the role of PEV in various cardiovascular diseases (such as atherosclerosis, myocardial infarction, ischemia-reperfusion injury, and heart failure), with relation to its molecular cargo (nucleic acids, bioactive lipids, proteins) and aims to provide new insights in the pathophysiologic role of PEV, and methods for preventing and treating cardiovascular diseases based on PEV.

Expert opinion: Studies have shown that the cargo of PEV may be dysregulated during cardiovascular disease and delivery to tissues can result in detrimental pathophysiologic effects. Counteracting this process might have the potential to inhibit inflammation, promote angiogenesis, and inhibit cardiomyocyte death. In addition, PEV have potential as biocompatible and autologous drug carriers. Therefore, better research on the mechanisms how PEV act during cardiovascular disease and could be implemented as a therapeutic will provide new perspectives for the treatment of cardiovascular disease.

Introduction: Tumor cell's resistance, high recurrence rate, and low overall survival rate have made hepatocellular carcinoma (HCC) a major health concern. The combination of advanced targeted therapies such as immunotherapy, with conventional treatments has gained traction for application on HCC. Immunotoxins (ITs) represent a category of biomolecules that combine the targeted affinity of antibodies with the cytotoxic properties of toxins.

Areas covered: This study highlights Glypican3 (GPC3) as a potential candidate for targeted therapeutic interventions using ITs. It presents a comprehensive overview of the advantages and challenges associated with these modalities, and their promising outcomes in HCC treatment. A systematic literature review was conducted using PubMed, Web of Science and Scopus from 2015 to 2024.

Expert opinion: Despite potential applicability, many concerns should be addressed before the employment of GPC3-based ITs. These include improving efficient penetration of ITs into the solid tumors, considering neutralizing antibodies against the drugs, and enhancing serum half-life of ITs. Furthermore, the ITs potential in eliminating cancer stem cells (CSCs) and residual tumor cells is discussed. The ability to target CSCs can significantly reduce the likelihood of recurrence and improve overall survival rate. This could make ITs a pivotal component in the future of HCC treatment.

Introduction: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease with a dismal prognosis. While the standard-of-care (SOC) drugs approved for IPF represent a significant advancement in antifibrotic therapies, they primarily slow disease progression and have limited overall efficacy and many side effects. Consequently, IPF remains a condition with high unmet medical and pharmacological needs.

Areas covered: A wide variety of molecules and mechanisms have been implicated in the pathogenesis of IPF, many of which have been targeted in clinical trials. In this review, we discuss the latest therapeutic targets that affect extracellular matrix (ECM) homeostasis and the activation of lung fibroblasts, with a specific focus on ECM invasion.

Expert opinion: A promising new approach involves targeting ECM invasion by fibroblasts, a process that parallels cancer cell behavior. Several cancer drugs are now being tested in IPF for their ability to inhibit ECM invasion, offering significant potential for future treatments. The delivery of these therapies by inhalation is a promising development, as it may enhance local effectiveness and minimize systemic side effects, thereby improving patient safety and treatment efficacy.