Expert Opinion on Drug Discovery最新文献

Introduction: The efficacy of current treatments for bacterial infections is under threat due to the continuing rise in the prevalence of antimicrobial resistance (AMR). Resistance can arise due to a wide variety of changes in the bacterial cell that prevent the antibiotic from acting on its target. This can be through changes to the target itself or changes that limit access to the target. Strategies to overcome resistance therefore either seek to reestablish access to the target or to engage a different target for which resistance is yet to arise. This has been done successfully in the clinic through co-dosing of more than one molecule, but a long-held aim has been to achieve efficacy in a single 'hybrid' molecule.

Areas covered: The authors review the progress since 2016 of hybrid antibiotics in clinical trials, cover some advances in preclinical research into dual-acting hybrids, and examine alternative approaches to using bi-functional hybrid molecules to tackle AMR.

Expert opinion: Many contributory factors, both scientific and economic, have limited the success of dual-acting hybrids where both partners are antibiotics. The success of cefiderocol highlights the potential of linking molecules that target bacteria directly and non-antibiotics. These strategies offer some exciting possibilities.

Introduction: Click chemistry, first introduced by Sharpless and colleagues in 2001, has been an essential tool of drug research owing to its modularity, high efficiency, excellent yields, chemoselectivity, and mild reaction conditions.

Areas covered: This review provides an overview of recent advances in drug development based on click chemistry over the past five years. It highlights key applications including fluorescent probes, lead identification and optimization, drug delivery systems, as well as emerging therapeutic modalities such as antibody-drug conjugates and protein degraders. The literature search was primarily conducted using PubMed and Web of Science.

Expert opinion: Click chemistry serves as a powerful enabler of accelerated drug discovery and development. Nevertheless, its clinical translation faces challenges such as physiological interference, pharmacokinetic requirements, and the potential toxicity of metal catalysts. Going forward, research should prioritize optimizing click chemistry reactions to enhance biocompatibility, safety, and stability. Meanwhile, combining click chemistry with artificial intelligence offers promise for identifying structurally diverse candidate molecules that are also synthetically feasible.

Introduction: Congestive heart failure (CHF) is a complex multi-organ syndrome representative of many chronic 'diseases,' and as such it has proven resistant to traditional cell-based drug discovery cannot readily be captured the relevant systemic biology. In vivo drug discovery screens offer unique opportunities to identify the initial dysfunction which ultimately drives heart failure (HF) and novel pathways modifying the cardiac response to injury.

Areas covered: In this review, the author discusses phenotype-driven screens which allow rigorous and unbiased approaches to the biological systems which underpin HF (PubMed search terms on 07/11/2025-heart failure, cardiomyopathy, zebrafish, screen, drug). The rationale for specific models of HF and the relevance of the zebrafish in screens for suppressors of HF is discussed. Central principles are detailed for the successful design and execution of phenotypic screens for HF modifiers. A major focus is the development of scalable HF assays in the zebrafish.

Expert opinion: In vivo phenotypic screening in the zebrafish is a reproducible approach to the identification of potent suppressors of complex multisystem disorders including different forms of HF. Design features associated with success are the rigor and human fidelity of the initial mechanistic modeling and quantitative screen endpoints.

Introduction: Psoriasis is a chronic, immune-mediated inflammatory skin disorder with a multifactorial pathogenesis involving keratinocyte proliferation, dysregulated immune responses, and vascular remodeling. The development of effective therapeutics mainly relies on preclinical models that can reproduce disease-relevant mechanisms.

Areas covered: This review outlines current in vivo psoriasis models, including spontaneous mutation models, transgenic and knockout mice, xenotransplantation systems, and cytokine-induced and imiquimod-induced models. Each model is evaluated for its ability to replicate key histological and immunological features of human psoriasis, such as acanthosis, immune cell infiltration, and cytokine network activation. The utility of CRISPR/Cas9 gene editing in generating targeted models is also discussed, thus highlighting its potential use for mechanistic studies. Finally, this review also emphasizes the limitations in translational applicability and the need for multimodel validation strategies regarding psoriasis. This article was based on a comprehensive literature search using PubMed, Scopus, and Google Scholar databases, covering publications from January 2015 to March 2025.

Expert opinion: Despite extensive model development, no single system fully mimics human psoriatic disease. The imiquimod-induced model remains widely used due to its practicality, although it better reflects acute inflammation compared with chronic pathology. The combination of complementary models and the incorporation of human-derived tissues or immune components may improve translational relevance. Advances in genome editing and humanized systems are likely to shape the future of psoriasis research and therapeutic discovery.

Introduction: Despite having a stably effectively vaccine for decades, the Measles virus (MV) still causes periodic outbreaks given its highly contagious nature and a consistent decline in immunization coverage, which was further exacerbated during the COVID-19 pandemic, leading to reduced immunization rates. Equally concerning, there are also no approved treatments for measles.

Areas covered: Herein, the authors explore the current challenges of MV therapy discovery. Firstly, the article will provide an overview of the potential drug-targeted steps in the MV infection process, followed by discussion on the characteristics of existing drugs as well as the feasibility of structure-based drug discovery. Finally, the authors highlight the current progress in the field and the future opportunities for antiviral development. This article is based on a literature review including original publications, standard sources, the Protein Data Bank and clinical trials.

Expert opinion: First and foremost, a comprehensive structural analysis of neutralizing antibodies and RdRp inhibitors is required for efficient antiviral development. Moreover, the therapeutic prospects and current limitations for acute MV and subacute sclerosing panencephalitis (SSPE) treatments should be considered. Due to various factors including mutations, the development of broad-spectrum antivirals may minimize many of the existing barriers.

Introduction: Fruquintinib is a novel oral tyrosine kinase inhibitor (TKI) with high selectivity for vascular endothelial growth factor receptors (VEGFR), which play a key role in tumor angiogenesis. Blocking this pathway represents an essential strategy in the continuum of care of patients with metastatic colorectal cancer (mCRC). Fruquintinib has been recently approved as monotherapy for refractory mCRC based on the FRESCO and FRESCO-2 pivotal trials, which demonstrated significant overall survival (OS) benefits compared to placebo, with manageable toxicity.

Areas covered: This article summarizes the preclinical development, pharmacology, clinical safety, and efficacy of fruquintinib in refractory mCRC patients and discusses current and future research to optimize its use as monotherapy and in combination with other treatments and potentially expand its use to earlier treatment lines and other types of cancer. A literature search (Dec 2024) was conducted in MEDLINE and EMBASE, and abstracts from major oncology conferences (AACR, ASCO, and ESMO) were reviewed.

Expert opinion: Fruquintinib expands the treatment armamentarium for patients with refractory mCRC, providing additional survival. Its high selectivity for VEGFR may minimize off-target effects, improving patients' safety and tolerability. Further research on combination strategies and biomarkers will be key to optimizing patient selection and broadening their clinical applications.

Introduction: Osteoporosis (OP) affects bone quality and quantity of millions of people worldwide. Osteoporotic fractures significantly decrease the quality of life of patients and are associated with increased mortality in the following years. Thus, there is continued clinical interest in treatments that preserve bone and mitigate fracture risk. As a routine method, several preclinical animal models exist to test current and potential OP treatments. However, most studies focus on trabecular bone, while cortical bone is under-studied, despite its significant role in bone strength and fragility.

Areas covered: The authors review the available on the use of the rabbit model to investigate the pathophysiology and treatments (antiresorptive and osteoanabolic) of OP, emphasizing cortical bone outcomes. Google Scholar was utilized to find the most up-to-date literature on the subject.

Expert opinion: The rabbit model of OP is suitable choice for investigation treatments in cortical bone, owing to its human-like cortical remodeling process, which is fundamental to the development of OP. Opportunities exist to utilize novel imaging and histological methods with the rabbit model to examine the mechanisms underpinning the pathophysiology of OP, and to investigate existing and new targets for drug discovery at a microscopic level within the cortical bone compartment.

Introduction: Kynurenine 3-monooxygenase (KMO) is a pivotal target in the kynurenine pathway (KP). KMO inhibitors (KMOis) decrease neurotoxic metabolites like 3-hydroxykynurenine and quinolinic acid while increasing neuroprotective kynurenic acid levels. It offers a promising therapeutic approach for treating neurodegenerative diseases, psychiatric disorders, acute pancreatitis, and immune-mediated conditions.

Areas covered: The authors provide an overview of the biology and function of KMO and highlight the key evidence for KMOi design. The authors also provide a summary of the structure - activity relationships (SARs) of several series of KMOis based on a comprehensive search of literature utilizing PubMed, Google Scholar, and Scopus, covering the period between 2015 and 2025. This works also provides explicit coverage to the chemical space of human KMOis (hKMOis), thereby providing a novel framework for the rational design of next-generation therapeutics targeting this enzyme.

Expert opinion: The KP, particularly KMO, has emerged as a compelling target for drug discovery. The Structure-Similarity Activity Trailing (SimilACTrail) map of hKMOis has provided novel insights for mapping the molecular landscape of hKMOis. A high scaffold-hopping rate (40.24%) underscores the potential for chemical innovation, while the identification of activity cliffs (0.58%) provides critical data for refining SARs. These findings offer a promising avenue for therapeutic development, with opportunities for the optimization of chemical scaffolds.

Introduction: Bisquinoline is a privileged pharmacophore in medicinal chemistry due to its diverse biological activities, particularly against infectious diseases such as malaria, tuberculosis, leishmania, fungi, bacteria, protozoa, schistosomiasis, and HIV. The success of piperaquine, a bisquinoline-derived antimalarial, has underscored its therapeutic potential, driving interest in its role as a small-molecule probe for targeting critical disease pathways. As drug resistance increases and the need for effective treatments rises, bisquinoline's broad pharmacological profile presents promising drug discovery opportunities.

Areas covered: This review explores research on bisquinoline derivatives as anti-infective agents, focusing on synthetic approaches, detailed structure-activity relationships, and therapeutic applications. It includes detailed insights into piperaquine, the only approved bisquinoline drug, based on literature from 2000 to 2025 sourced from PubMed, Scopus, and Web of Science concerning 'bisquinoline scaffold' keywords.

Expert opinion: In the last two decades, significant progress has been made in developing bisquinoline derivatives with various pharmacological effects. These advancements have expanded our understanding of the scaffold's pharmacological diversity and its potential for creating more effective drugs with fewer side effects. This continued progression will aid the development of the next-generation of bisquinoline-based therapeutics.