Drug Discovery Today最新文献

Conventional antibodies [full-length and fragments: F(ab')2, fragment antigen-binding (Fab), single-chain variable fragment (scFv), variable heavy domain of heavy chain (VHH)] are monospecific first-generation antibodies that have dominated the biopharmaceuticals field. However, advanced protein engineering technology has led to the advent of the next-generation polybody, which is a significant improvement over the conventional antibody. Polybodies comprise polyspecific and polyvalent antibodies that enable a single antibody to target multiple specific antigens simultaneously. Polybodies are superior to first-generation antibodies (more efficacious, broad-spectrum, resistance resistant, customizable, etc.) and provide a cost-effective healthcare solution. This review thoroughly addresses developments in polybodies, highlighting their superiority over conventional antibodies and offering future perspectives to encourage the generation of innovative immunotherapies.

Cryptic sites can expand the space of druggable proteins, but the potential usefulness of such sites needs to be investigated before any major effort. Given that the binding pockets are not formed, the druggability of such sites is not well understood. The analysis of proteins and their ligands shows that cryptic sites that are formed primarily by the motion of side chains moving out of the pocket to enable ligand binding generally do not bind drug-sized molecules with sufficient potency. By contrast, sites that are formed by loop or hinge motion are potentially valuable drug targets. Arguments are provided to explain the underlying causes in terms of classical enzyme inhibition theory and the kinetics of side chain motion and ligand binding.

Light-sheet fluorescence microscopy (LSFM) combined with tissue clearing has emerged as a powerful technology in drug discovery. LSFM is applicable to a variety of samples, from rodent organs to clinical tissue biopsies, and has been used for characterizing drug targets in tissues, demonstrating the biodistribution of pharmaceuticals and determining their efficacy and mode of action. LSFM is scalable to high-throughput analysis and provides resolution down to the single cell level. In this review, we describe the advantages of implementing LSFM into the drug discovery pipeline and highlight recent advances in this field.

The heat shock protein 110 (Hsp110) family in eukaryotes plays a pivotal role in maintaining cellular proteostasis. As a unique class of molecular chaperones, Hsp110s act as both independent chaperones and cochaperones for other essential molecular chaperones. Malfunction of Hsp110s is involved in many diseases. Thus targeting Hsp110s or its interactions with client proteins may provide new approaches for developing therapeutics. In this review, we describe the current understanding of the role and molecular mechanism of Hsp110s in disease development, and discuss the recent exploration of Hsp110s as potential targets to provide a novel direction for disease diagnosis and targeted therapy.

Early toxicity assessment plays a vital role in the drug discovery process on account of its significant influence on the attrition rate of candidates. Recently, constant upgrading of information technology has greatly promoted the continuous development of toxicity prediction. To give an overview of the current state of data-driven toxicity prediction, we reviewed relevant studies and summarize them in three main respects: the features and difficulties of toxicity prediction, the evolution of modeling approaches, and the available tools for toxicity prediction. For each approach, we expound the research status, existing challenges, and feasible solutions. Finally, several new directions and suggestions for toxicity prediction are also put forward.

Post-translational modifications (PTMs) of proteins are crucial for regulating biological processes and their dysregulation is linked to various diseases, highlighting PTM regulation as a significant target for drug development. Traditional drug targets often interact with multiple proteins, resulting in lower selectivity and inevitable adverse effects, which limits their clinical applicability. Recent advancements in bifunctional molecules, such as proteolysis-targeting chimeras (PROTACs), have shown promise in targeting PTMs precisely. However, regulatory mechanisms for many of the >600 known PTMs remain underexplored. This review examines current progress and challenges in designing bifunctional molecules for PTM regulation, focusing on effector selection and ligand design strategies, aiming to propel the utilization and advancement of bifunctional molecules to the forefront of PTM research.

Innate immunity plays an important role in host defense against pathogenic infections. It involves macrophage polarization into either the pro-inflammatory M1 or the anti-inflammatory M2 phenotype, influencing immune stimulation or suppression, respectively. Epigenetic changes during immune reactions contribute to long-term innate immunity imprinting on macrophage polarization. It is becoming increasingly evident that epigenetic modulators, such as histone deacetylase (HDAC) inhibitors (HDACi), enable the enhancement of innate immunity by tailoring macrophage polarization in response to immune stressors. In this review, we summarize current literature on the impact of HDACi and other epigenetic modulators on the functioning of macrophages during diseases that have a strong immune component, such as infections. Depending on the disease context and the chosen therapeutic intervention, HDAC1, HDAC2, HDAC3, HDAC6, or HDAC8 are particularly important in influencing macrophage polarization towards either M1 or M2 phenotypes. We anticipate that therapeutic strategies based on HDAC epigenetic mechanisms will provide a unique approach to boost immunity against disease challenges, including resistant infections.

A new fate of cell surface receptors, cleaved activation in the nucleus, is summarized. The intracellular domain (ICD) of cell surface receptors, cleaved by enzymes like γ-secretase, translocates to the nucleus to form transcriptional complexes participating in the onset and development of tumors. The fate is clinically significant, as inhibitors of cleavage enzymes have shown effectiveness in treating advanced tumors by reducing tumorigenic ICDs. Additionally, the construction of synthetic receptors also conforms with the fate mechanism. This review details each step of cleaved activation in the nucleus, elucidates tumorigenic mechanisms, explores application in antitumor therapy, and scrutinizes possible limitations.

MicroRNA-29b (miR-29b) is known for its therapeutic potential as an antifibrotic and anticancer agent. In fibrotic conditions, miR-29b inhibits fibrogenesis by downregulating crucial regulators such as collagens, extracellular matrix proteins and the transforming growth factor-β pathway. Similarly, in cancer, it acts as a tumor suppressor by downregulating various oncogenes and signaling pathways involved in cancer progression, such as Wnt-β-catenin, p38-mitogen-activated protein kinase and nuclear factor-κB. However, the upregulation of these pathways suppresses miR-29b, contributing to fibrosis and cancer development. Preclinical research and clinical trials have shown that delivering exogenous miR-29b mimics can restore its expression, attenuating tumorigenesis and fibrogenesis. This review discusses miR-29b's potential and its possible therapeutic development for cancer and fibrotic disorders.