Application of bioactive small molecules in disease research

Small molecule compounds refer to compounds with a molecular weight less than 1000Da (especially less than 500Da) and biological activity. Unlike cytokines and proteins, small molecule compounds can enter cells through the cell membrane and perform corresponding biological functions. Small molecule compounds have many targets and have been widely used in many important research fields in life sciences, such as oncology, immunology, neurobiology, epigenetics, stem cells, organoids, cell apoptosis, ion channels, and signal transduction.

Small molecule compounds mainly exert their effects by regulating the activity of their protein targets. At present, the protein targets of small molecule compounds mainly include three categories: enzymes, ion channels, and receptors.

Table 1 Classification and mechanism of action of small molecule compounds

Application of Active Small Molecules in Disease Research

Case 1: In tumor immunotherapy research, the active small molecule Brefeldin A is used to block cytokine transport.

In the study of mouse primary T cell isolation and effector function analysis, in order to detect the secretion of cytokines interferon - γ (IFN - γ), tumor necrosis factor (TNF), and granzyme B (GzmB), researchers treated cells with 5 μ g/mL Brefeldin A for 5 hours before cell harvesting to block cytokine transport.

Figure 1: WT and cKO CD8+T cells were stimulated with anti-CD3/CD28 (0 or 2 μ g/mL) for 96 hours, and treated with Brefeldin A (5 μ g/mL) for 5 hours to produce IFN - γ, TNF, and GzmB (n=3)

References: ERK and USP5 govern PD-1 homeostasis via deubiquitination to modulate tumor immunotherapy[J]. Nature Communications, 2023, 14(1). DOI:10.1038/s41467-023-38605-3.

Impact factor (IF): 17.694

Case 2: In the study of regulating the dynamic balance of aging intestines, the use of active small molecule Genistein in mouse diet can improve intestinal dysfunction.

Researchers used wild-type aging mice and Zmpste24-/- premature aging mice to investigate the role of genistein in the lifespan and dynamic balance of mammalian aging intestines. They found that dietary genistein can increase the levels of short chain fatty acids derived from the microbiota, regulate the dynamic balance of the aging gut, and prolong health and lifespan. In addition, the association between genistein and gut microbiota provides a theoretical basis for dietary intervention in age-related frailty.

Figure 2: Dietary Genistein Improves Intestinal Dysfunction in Aging Mice

References: Dietary genistein increases microbiota-derived short chain fatty acid levels, modulates homeostasis of the aging gut, and extends healthspan and lifespan[J]. Pharmacological Research, 2023. DOI:10.1016/j.phrs.2023.106676.

Impact factor (IF): 10.334

Case 3: When exploring the role of SIRP α in lung cancer growth, the active small molecule SB203580 was used as a p38 MAPK pathway inhibitor

Researchers established wild-type (WT) and Sirp α gene knockout mouse (KO) lung cancer models by subcutaneous injection of Lewis mouse lung cancer cells. Analyze the phenotype and phagocytic function of macrophages and neutrophils using flow cytometry. Research has shown that Sirp α reduces the phagocytic function of M1 subtype macrophages through the SHP-1/p38MAPK/STAT3 signaling pathway.

Figure 3: Lack of SIRP α promotes macrophage phagocytic function through SHP-1/p38MAPK/STAT3 signaling pathway

References: Lack of SIRP-alpha reduces lung cancer growth in mice by promoting anti-tumour ability of macrophages and neutrophils[J]. Cell Proliferation. 2022. DOI: 10.1111/cpr.13361.

Impact factor (IF): 8.755

Active small molecules have broad application prospects in disease research, and they can be used in multiple fields such as drug discovery, pharmacology research, establishing disease models, and gene and cell therapies. By gaining a deeper understanding of the characteristics and functions of active small molecules, as well as their advantages and value in disease research, we can better recognize their important position in scientific research and look forward to more breakthroughs brought by active small molecules in the fields of scientific research and disease treatment!