Expert Opinion on Drug Discovery最新文献

Introduction: Methicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of severe infections with excess mortality and rising resistance. Progress with traditional antibiotics has been incremental, while resistance, persistence, tolerance, and biofilm formation continue to erode effectiveness. Parallel advances in small-molecule discovery, long-acting lipoglycopeptides, next-generation β-lactams, and non-traditional modalities such as bacteriophage lysins have renewed interest in expanding therapeutic options, though transition from promising preclinical signals to clinical benefit remains challenging.

Areas covered: A literature search was conducted using PubMed/MEDLINE, and Embase, for articles published from January 2010 through March 2025, focusing on clinical, translational, and preclinical developments in MRSA therapeutics. This review synthesizes developments across: (i) agents in key clinical trials for invasive MRSA infection, emphasizing on trial designs, efficacy, and safety considerations; (ii) clinical study data with newer agents for MRSA skin infections and their potential application in invasive disease; (iii) preclinical pipelines including natural products, novel compounds, and other innovative antimicrobial strategies under investigation.

Expert opinion: Among clinical stage investigated agents, ceftobiprole, ceftaroline, dalbavancin, and exebacase represent promising options for invasive MRSA infections. The pipeline is further strengthened by novel classes and antimicrobial peptides, which show anti-MRSA activity and a low risk for resistance as demonstrated in preclinical models. Continued multidisciplinary collaboration and robust clinical trial infrastructure are essential to translate these advances into improved patient outcomes.

Introduction: Small open reading frame-encoded peptides (SEPs) are short peptides translated from small open reading frames (sORFs) that were previously overlooked in genome annotations. SEPs have relatively small molecular sizes, fewer than 100 amino acids, some SEPs can be as short as a dozen amino acids. Recent studies have revealed their widespread presence across plants, animals, and microorganisms, as well as their diverse biological functions and potential applications.

Areas covered: This review introduces the characteristics and biogenesis of SEPs, the processes and methods for their identification and validation, and their functional roles and target sites, highlighting the significant potential of SEPs in biological research and therapeutic development. Relevant literature was identified on PubMed (2010-2025) by searching for 'SEP,' 'sORF,' and 'Microprotein.'

Expert opinion: The revolutionary advances in high-throughput omics technologies - particularly mass spectrometry and ribosome profiling - combined with computational prediction methods such as machine learning, have enabled the discovery of an increasing number of SEPs. Research on SEP is currently in a phase of rapid development, and this suggests that the field of peptide drugs may gain many promising molecular candidate.

Introduction: Dengue virus (DENV) remains a significant global health threat, causing millions of infections and substantial morbidity each year. The viral E protein is a key target for neutralizing antibodies and vaccine design; however, antibody-dependent enhancement (ADE) complicates safe immunization. Currently licensed vaccines offer only partial and serotype-dependent protection, highlighting the urgent necessity for additional therapeutic strategies.

Areas covered: This review summarizes advances in direct-acting antivirals (DAAs) targeting the E protein and host-directed therapies (HDTs). It discusses DAAs that block E-mediated viral entry and HDTs that modulate lipid metabolism, nucleotide biosynthesis, protein folding, translation, and immune pathways. Promising preclinical candidates and experimental DAAs-HDTs combinations with synergistic activity are highlighted, alongside persistent challenges related to viral diversity, ADE risk, host toxicity, and translational limitations. Relevant literature was identified through PubMed, Scopus, Web of Science, ClinicalTrials.gov, and WHO databases, including recent and foundational studies up to September 2025.

Expert opinion: Combining DAAs with HDTs represents a rational strtategy to enhance antiviral efficacy, broaden serotype coverage, reduce resistence, and pontentially limit toxicity. Although clinical evidence remains limited, expandend preclinical and clinical evaluation of these approaches, incorporating serotype-specific testing and sex-based analyses will be essential for advancing effective dengue therapeutics.

Introduction: Structural biology has become a cornerstone of modern drug discovery, enabling atomic-level insights into protein - ligand interactions and guiding rational therapeutic design. As the field evolves, it faces growing demands for accuracy, reproducibility, and integration with computational and pharmacological data.

Areas covered: This article explores the impact of sample heterogeneity and radiation damage on macromolecular crystallography, emphasizing how these factors can compromise structural integrity. It reviews current strategies for mitigating crystal damage, including optimized cooling, dose-aware data collection, and emerging technologies such as serial crystallography and advanced detectors. The manuscript also discusses the limitations of existing validation tools and the need for improved metadata reporting to ensure reliable structural models. Cryo-electron tomography is highlighted as a promising technique for studying drug - target interactions in native cellular environments, offering complementary insights to traditional crystallographic methods.

Expert opinion: To advance drug discovery, the structural biology community must adopt unified standards for data validation and experimental documentation. High-quality, reproducible structures are essential for minimizing artifacts and supporting AI-driven modeling and screening. A coordinated effort to integrate damage-aware practices and metadata standards will enhance the fidelity of structural data and its utility in therapeutic innovation.

Introduction: Efficient structure-based design requires robust protocols for generating protein-ligand complex structures to support iterative chemical optimization. However, developing reliable crystallization conditions suitable for drug discovery remains challenging, especially for novel targets and when working with diverse ligand classes.

Areas covered: The review focuses on establishing robust crystallization workflows and providing solutions when standard methods prove inadequate for obtaining protein-ligand crystal structures. In addition to reviewing the literature for generic technical advances, the authors provide a comprehensive overview of project- and protein-specific approaches. To further substantiate their claims, the authors analyzed metadata from their proprietary structure collection, representing 20 years of crystallography supporting structure-based drug design. The authors provide two detailed examples showcasing rescue strategies in action.

Expert opinion: Crystal structures will remain fundamental to structure-based drug design moving forward. Successful crystallization demands adaptable, multi-faceted strategies that systematically explore diverse protein variants and crystallization conditions. Future progress depends on integrating AI tools for construct design with project insights and robust experimental workflows. Success ultimately hinges on synergy between innovative problem-solving approaches and deep expertise in navigating this rapidly evolving landscape.

Introduction: Ebolavirus (EBOV) is a highly pathogenic member of the Filoviridae family, causing severe hemorrhagic fever with high mortality rates and is persistent threat to global health with recurrent outbreaks. Although advances, including vaccine and monoclonal antibody therapeutic development, have improved survival chances, challenges such as cost and availability remain as well as potential viral evolution. Consequently, there is an urgent need for alternative, cost-effective and scalable therapeutics, which has driven interest in computational drug discovery as rapid response strategies.

Area covered: This review synthesizes structural and functional insights into EBOV's key molecular targets and explores their roles in viral entry, replication, and immune evasion. The authors also discuss host-pathogen interactions as potential therapeutic routes of entry and present the most recent computational advances for hit identification and optimization. There is also coverage given to case studies highlighting successful in silico discovery efforts. Literature identified via PubMed, Scopus, and Web of Science were utilized to compose this manuscript with the authors focusing on on recently published studies, while also utilizing their own experience and insight.

Expert opinion: While promising, translation of Ebola viral research remains limited by incomplete structural coverage, small and imbalanced datasets, and a gap between computational prediction and experimental validation. Hybrid in silico workflows are embedded within standardized, data-driven, and experimentally anchored pipelines, and are essential to bridge this gap. By uniting computational precision with laboratory validation, integrative strategies can accelerate the development of robust, deployable EBOV therapeutics and serve as a model for pandemic preparedness against other high-risk pathogens.

Background: Carbapenemase-producing Klebsiella pneumoniae severely limits treatment options by inactivating carbapenem and other β-lactam antibiotics. To support precision drug discovery, this study investigates how structural and dynamic differences among major carbapenemase families shape their interaction with carbapenem drugs.

Research design and methods: The authors performed an in-silico analysis of five key Klebsiella pneumoniae carbapenemases (KPC, NDM, VIM, IMP, OXA-48) using multiple sequence alignment, homology modeling, molecular docking, and 50-ns molecular dynamics simulations.

Results: Sequence identity between variants was low (33.8-48.5%), indicating deep evolutionary divergence. SWISS-MODEL homology models showed high stereochemical quality, supporting reliable active-site interpretation. Docking suggested stronger binding of meropenem and imipenem to KPC and NDM, mediated by conserved catalytic residues in class A (Ser70, Lys73, Glu166) and class B (His120, His122, Asp124). MD simulations indicated more rigid, compact complexes for KPC and NDM, contrasted with higher flexibility in OXA-48.

Conclusions: These results reinforce that Klebsiella pneumoniae carbapenemases are not interchangeable targets and that inhibitor design must account for family-specific active-site geometries and dynamics. Integrating such structural insight with future virtual screening and experimental validation could enable variant-tailored inhibitors rather than relying on a single broad-spectrum carbapenemase blocker.

Introduction: Fluorinated amino acids are at the focal point of two key current strategic areas within drug discovery being both important for the design/development of new small molecule drugs as well as having the potential to be exploited in the rapidly expanding area of peptide-based therapeutics. While the challenges of developing therapeutic peptides are relatively well understood and strategies have been developed to overcome these, the utilization of fluorinated amino acids for this purpose appears to be relatively sparse, particularly in progressing peptide derivatives into clinical development.

Areas covered: This review discusses the applications of fluorinated amino acid (FAA) derivatives in modern drug discovery with a specific focus on their incorporation into therapeutic peptide derivatives, based on the currently available literature.

Expert opinion: While only one naturally occurring and fluorinated amino acid (FAA) is known, the use of this class of compounds is prevalent in drug discovery campaigns. Synthetic advances have allowed ready access to a diverse range of compounds featuring this structural motif, and the bifunctional modularity of the amino and carboxylic acid moiety typically allows their ready incorporation into novel molecular entities through well-precedented chemistries. However, caution should be exercised when FAAs are utilized in solid-phase peptide synthesis (SPPS) as the electronegativity of the fluorine substation often mitigates the reactivity of the system leading to poor yields. Future efforts should look toward developing a more reliable understanding of the impact of these changes to enable a robust platform for therapeutic peptides to be designed based on the incorporation of fluorinated amino acids.

Introduction: In recent years, progress in developing peptide-based therapeutics from natural peptide hormones has significantly advanced obesity treatment. By harnessing the body's natural peptide hormonal mechanisms, these GLP-1-based therapies have achieved impressive weight loss of 15-25%, once thought impossible, while also demonstrating excellent safety. Such weight loss levels were previously believed to be only achievable through bariatric surgery, marking a significant shift in managing diabetes, obesity, and related health issues.

Areas covered: This review explores how the emergence of second-generation peptide therapeutics was driven by advances in fatty acid technology combined with backbone engineering to achieve once-weekly dosing intervals, as well as by unimolecular dual and poly-agonists targeting pathways beyond GLP-1 receptor signaling.

Expert opinion: Although these innovations offer renewed hope in the fight against obesity, they also pose challenges. Barriers to widespread adoption and access still exist, especially in manufacturing peptide therapeutics, which need significant investments in production infrastructure to reach more than hundreds of millions of patients worldwide.