Identification and optimization of novel inhibitory compounds in Ganoderma through human formyl peptide receptors

汪会荣

11553012

博士

Biomedical Sciences

黄巍

2020-07-09

2020-07-20

澳门大学

澳门

Formyl peptide receptors (FPRs) belong to G protein-coupled receptors (GPCRs) that play important roles in host defense, inflammation and the pathogenesis of infectious and inflammatory diseases. They are widely expressed in various types of multicellular tissues and circulating blood cells, especially on neutrophils and other phagocytes. Meanwhile, FPRs regulate several major cellular functions in inflammation resolution and various diseases, thereby they can be considered as potential targets for antagonizing inflammatory responses in certain diseases and even cancer. Inhibiting FPRs may be a novel strategy for the treatment of systemic inflammatory response syndrome (SIRS) or sepsis.In order to search for potentially novel anti-inflammatory drugs, we examined Ganoderma (Lingzhi), a Chinese medicinal herbs known for its various therapeutic benefits, including antibacterial, anticancer effects and immune-regulatory effects, and found that compound C18 derived from Ganoderma cochlear could limit inflammatory response through FPR-mediated signaling pathways. Further studies showed that C18 could bind to FPR2 and induce different conformational changes of the receptor compared with its pan-agonist, WKYMVm. C18 induced conformational change of FPR1 similarly to that of fMLF. These interactions block some key amino acids in the active sites of FPRs that are crucial for receptor activation, leading to reduced production of superoxide and compromised cell chemotaxis, thus relieving the symptoms of inflammation.Although C18 mainly targets FPR2, the results also indicated that FPR1 was involved and might have a different mechanism from FPR2. Therefore, FPR1/FPR2 heterodimer and FPR2/FPR2 homodimer mediated signaling pathways were considered, and the results confirmed that C18 induced FPR dimers-mediated anti-inflammatory cytokine release or PMN apoptosis. Thesis activities further accelerate the resolution of inflammation. Considering that the IC50 of C18 is not ideal, it is necessary for optimizing the lead compound C18. Based on information from the previous studies, a series of C18 derivatives were synthesized and their biological activities were determined. Subsequently, in order to provide reasonable suggestions for further optimization of the lead compound, the structure and biological properties of these derivatives were quantified with three-dimensional quantitative structure-activity relationship (3D-QSAR). And two derivatives of the compounds, D31 and D34 that showed higher biological activity and lower toxicity than C18, were utilized to reveal the detailed interactions with FPR2 through molecular docking studies. In summary, our studies firstly discovered a Ganoderma-derived component with inhibitory effects that acts through a G protein-coupled receptor FPR2 and revealed the mechanism of this compound with various functional assays. Subsequently the structure and biological properties of the C18 derivatives were quantified to establish a 3D-QSAR model, which provides clues for further optimization of the lead compound. Besides, two derivatives with better IC50 and lower cytotoxicity were analyzed by molecular docking to explain the detailed interactions with the receptor, which need to be further investigated in future animal models.

Formyl peptide receptors Ganoderma anti-inflammatory chemotaxis superoxide

英语

联合培养

南方科技大学

Wang HR. Identification and optimization of novel inhibitory compounds in Ganoderma through human formyl peptide receptors[D]. 澳门. 澳门大学,2020.