Research reagents-brand new compounds are expected to become fungus nemesis
With the increase of immunodeficiency patients, the widespread development of organ transplantation and interventional diagnosis and treatment, and the widespread application of antibacterial drugs and chemotherapy drugs, the incidence of systemic fungal infections is increasing year by year. But at the same time, the clinical use of a large number of limited antifungal drugs has also made fungal resistance increasingly serious. Not long ago, with the support of the National Natural Science Foundation of China, Jiang Yuanying, Dean of the School of Pharmacy of the Second Military Medical University of the PLA, led scientific researchers to independently develop 2-aminotetrahydronaphthalene compounds, which is expected to improve this situation in the future. China Pharmacology News. "2-Aminotetrahydronaphthalene compounds have a completely different chemical structure from existing antifungal drugs. Although they are also similar to azole drugs, they exert an effective antifungal effect by inhibiting ergosterol, an important structural component of fungal cell membranes, but Its action target is completely different from azole drugs. "A few days ago, Cao Yongbing, an associate professor of the School of Pharmacy of the Second Military Medical University who participated in the research, accepted an interview with the" Science Times ". Drug resistance and toxicity stimulate new drug research Fungi are a large class of eukaryotic cell-type microorganisms with cell walls and eukaryotic structures that do not distinguish roots, stems, and leaves, and contain no chlorophyll. They exist in nature in a parasitic or saprophytic manner and can reproduce sexually or asexually. According to relevant information in the United States, invasive Candida infection has become one of the four most common bloodstream infections in the United States, and invasive aspergillosis has become the main cause of death in severely immunocompromised bodies of leukemia and bone marrow transplant recipients. In addition to the increasing number of common pathogenic fungal infections, some rare or rare fungal infections are also reported from time to time. Therefore, more and more clinical and scientific research are focusing on the prevention and treatment of fungal infections. At present, the most commonly used antifungal drugs in clinic are polyenes and azoles. Azazoles are the most widely used antifungal drugs in clinical practice, mainly acting on lanosterol demethylase in the ergosterol biosynthetic pathway, but these drugs can bind to the heme iron atom of mammalian cells and cause severe liver and kidney poison. Candida is also the most common drug resistance to fluconazole and other commonly used antifungal drugs such as azoles, which has become a major problem in the prevention and treatment of systemic fungal infections. In addition, polyene drugs are the "gold standard" for the treatment of severe fungal infections, but their severe acute and chronic adverse reactions, such as hemolysis and renal failure, limit its clinical use. Cao Yongbing said that in recent years, the incidence of systemic fungal infections has increased significantly, and drug-resistant strains in common strains that cause systemic fungal infections have been expanding. Systemic fungal infections are associated with a decrease in the body's immune function. Because the patient's immune function is severely impaired, even with strong empirical antifungal treatment, the prognosis is still poor, with a case fatality rate of more than 70%. "But for many years, the research hotspots of new antifungal drugs have mainly focused on the improvement of polyene formulations and the structural transformation of azoles, and they have not been able to fundamentally overcome the toxicity problems of the above-mentioned drugs. New drugs with targeted targets are the way out for the development of highly effective and low-toxic antifungal drugs. "Cao Yongbing said. Find new drug targets "Some large foreign pharmaceutical companies are also constantly researching new antifungal drugs. Drug targets have effects on cell membranes and cell walls, but the prices of these drugs are generally relatively high, and they still produce drug toxicity." Cao Yongbing said, The target of drug action discovered in this study is the first time at home and abroad. According to Cao Yongbing, the target of the original azole drugs is the P450 enzyme in the fungus. The P450 enzyme has a detoxifying effect, and it can usually metabolize fat-soluble toxic substances into water-soluble substances, so that the toxic substances are eliminated from the body. Cao Yongbing explained: "P450 enzymes exist in various organisms, and this enzyme is also found in human livers. Nitrozole drugs, while killing fungi, also destroy P450 enzymes in human livers, resulting in drug toxicity." "The original intention of our research was to avoid the target enzymes of the original drugs and find new targets. With the deepening of the research, we found that the use of 2-aminotetrahydronaphthalene compounds in fungi Another enzyme can also work without hepatotoxicity. "Cao Yongbing said. Researchers used gas chromatography-mass spectrometry (GC / MS) and other technologies to analyze the most antifungal compound 2-aminononane-6-methoxytetrazine among the currently known 2-aminotetralins The effect of hydronaphthalene hydrochloride (10b) on Candida albicans ergosterol organisms. The results showed that 2-aminononane-6-methoxytetrahydronaphthalene hydrochloride significantly reduced the activity of ergosterol biosynthesis by double inhibiting the activities of sterol C-14 reductase and C-5 desaturase-related enzymes, thus Destroy the integrity of cell membranes and cause fungal death. Cao Yongbing said that MTS / PMS reduction analysis showed that although 2-aminononane-6-methoxytetrahydronaphthalene hydrochloride can dose-dependently reduce mammalian cell activity, it has the lowest inhibitory concentration against Candida albicans Far lower than the minimum inhibitory concentration on mammalian cells, this provides a preliminary safety guarantee for possible future human studies of 2-aminononane-6-methoxytetrahydronaphthalene hydrochloride. Need to continuously improve later Experts believe that 2-aminotetrahydronaphthalene compounds are highly efficient, broad-spectrum, low-toxic, and have a unique mechanism of action, which avoids liver and kidney toxicity caused by the combination of heme iron atoms with azole drugs. In addition, because its chemical structure is different from the existing antifungal drugs, these compounds will also effectively overcome the increasingly severe clinical fungal drug resistance problems. However, Cao Yongbing believes that this is just the beginning, and the improvement of 2-aminotetralin compounds in the future still needs to be continuously carried out. "Compared with existing drugs, the current activity of these compounds is not strong enough, and there is no antifungal drug currently used. The activity is also large. In addition, this can only be called a compound, not a drug. Because, this Whether the enzymes that the compounds act on overlap in different organisms needs to be studied. "Cao Yongbing said. Although there is still a lot of follow-up research work, this study of the School of Pharmacy of the Second Military Medical University of the PLA has laid the foundation for the development of new antifungal drugs. Cao Yongbing believes that this has benefited from the increasing intensity of fund support in recent years. "In the past, the investment in the research and development of a new drug was only 100,000 to 200,000 yuan. Now it can reach several million yuan or even tens of millions of yuan. In addition, there are more projects that can be applied for. It has now reached more than 10,000. Research units have more research funding, which has greatly increased the enthusiasm of researchers and made the development of new drugs much faster than in the past. "Cao Yongbing has Personal feelings. "We will continue to try new discoveries in the future and strive for new breakthroughs in drug research and development." Cao Yongbing said Kitchen Gadgets And Accessories Kitchen Gadget Set,Kitchen Tools Accessories,Silicone Kitchen Gloves,Kitchen Gadgets And Accessories Yangjiang Yado Kitchen Industry Co., Ltd. , https://www.yadokitchen.com