Nature: Fudan University has identified four kinds of autophagy linking compounds, which are expected to treat polyQ diseases such as Huntington chorea

November 18, 2019 / BIOON / - -- Huntington's disease (hd) is one of the four major neurodegenerative diseases that have been widely studied Its clinical symptoms include uncontrollable dance like behavior (i.e chorea), cognitive deficit and mental disorder In view of the fact that the biochemical activity of the Huntington protein mutant (mutant huntingtin, mhtt, mutant htt) that causes this disease has not been characterized, it is not feasible to find inhibitors that block the biological activity of these pathogenic proteins by traditional drug discovery methods Picture from nature, 2019, DOI: 10.1038/s41586-019-1722-1 In a new study, researchers from Fudan University in China are working to solve the problem They have developed an innovative drug discovery method: using autophagosome tethering compound (attec) to degrade pathogenic proteins and treat the disease They carried out a clever design of screening: using small molecular microarray and cutting-edge optical technology, they successfully identified four small molecular compounds, all of which can specifically reduce the protein causing Huntington's disease Relevant research results have been published in nature recently, and the title of the paper is "allele selective lowering of muttant htt protein by htt – LC3 linker composites" The corresponding authors are Professor Yu Ding, Professor Yiyan Fei and Professor Boxun Lu of Fudan University The first authors of this paper are Zhaoyang Li, cen Wang, Ziying Wang and Chenggang Zhu from Fudan University Small molecular glue can help autophagy to "phagocytize" pathogenic proteins Because traditional methods are not feasible for mhtt, these researchers have proposed a new idea, that is, to degrade mhtt through autophagy, the process of protein degradation in cells In the process of autophagy, LC3, a key protein, is liposylated and expanded into a bimembrane structure, which then engulfs proteins, lipids, organelles and other degradation products and forms a complete autophagy Autophagosomes then fuse with lysosomes and the phagocytic material is degraded However, in the event of nonspecific enhancement, autophagy degrades all proteins engulfed in autophagy, including the normal wild-type Huntington protein (HTT), which plays a role in neuroprotection This can be self defeating To identify compounds that degrade only mhtt but not wild-type htt, the researchers envisioned a "small molecule gel" that acts as an "autophagic linker compound" (attec) that binds LC3 to mhtt, allowing mhtt to be engulfed in autophagy for subsequent degradation At the same time, attec does not interact with wild-type htt protein, so it does not affect wild-type htt protein By screening, verifying and initially searching for compounds with similar structures, they identified four compounds with required properties At this point, the four identified compounds have the potential to connect mhtt to autophagy without affecting wild-type htt, but whether they do play a role in the degradation of mhtt as expected needs further verification The researchers found that these four compounds significantly reduced mhtt levels in neurons of HD mice, HD patient cells and HD Drosophila models at a concentration of about 10-100 nm, and had little effect on wild-type htt levels It is exciting that at least two of the four compounds can cross the blood-brain barrier, and low dose intraperitoneal injection can significantly reduce mhtt levels in the cortex and striatum of HD mice, without affecting the level of wild-type htt They also significantly improve disease-related phenotypes, which provides an entry point for the development of oral or injection HD drugs Identifying such attec is challenging Only one of about 2000 compounds has the required properties Therefore, it has long been found that attec is the main obstacle to this research project The participation of Professor Yiyan Fei's research group at Fudan University makes this possible Yiyan Fei research group has developed a new high-throughput compound screening platform based on small molecular microarray and oblique incidence reflectivity difference (oi-rd) technology The platform is fast, sensitive, unmarked and high-throughput It can identify the compounds interacting with the target protein from the chemical library composed of thousands of small molecular compounds The researchers imprinted nearly 4000 small molecular compounds on the chip and let the target protein flow through the chip If the sample is combined with a specific compound fixed on the chip, the molecular layer at that location will become thicker, which will produce small changes that can be detected by sensitive optical methods (i.e., oi-rd) Using this state-of-the-art screening method, they found two small molecules that bind to LC3 and mhtt proteins but not to wild-type htt After studying a group of small molecular compounds with similar structure, they identified and verified four attec combining LC3 and mutant htt Autophagy linked compounds may open a new window for drug discovery These researchers further explored the internal mechanism that these small molecular compounds can distinguish between mutant and wild-type htt proteins, in which the mutant and wild-type htt proteins are almost the same except for the differences in the length of glutamine repeat sequence (polyQ) The results showed that these compounds combined with the long polyQ fragment which only appeared in mhtt Based on this, the researchers realized that the application of these small molecular compounds may be far beyond the potential treatment of Huntington's disease Nine human diseases are known as polyQ diseases because they are all caused by a specific mutant protein that contains an overly long polyQ Among the nine diseases, spinocerebellar ataxia type III (SCA3) is the most common in Chinese population The clinical symptoms of SCA3 include uncoordinated movement, inability to maintain body posture and balance, and possible exophthalmos, hyperreflexia, facial muscle twitch, tendon symptoms and other symptoms Using SCA3 patient cells provided by Dr Yimin sun from Professor Jian Wang's research group of Huashan Hospital Affiliated to Fudan University, the researchers found that these compounds can effectively reduce the level of atxn3 protein mutant (polyQ length 74, i.e with 74 glutamylamines) that causes the disease without affecting the wild-type atxn3 (polyQ length 27) When it comes to the future development and application of this research, Professor Boxun Lu of the school of life sciences at Fudan University said: "these compounds can not only effectively treat Huntington's chorea, but also other polyQ diseases The concept of drug development using autophagic conjugates can also be applied to other pathogenic proteins without drug targeting, and even to non protein pathogenic substances, such as organelles or lipids " (BIOON Com) reference: 1 Zhaoyang Li et al Allele selective lowering of mutton htt protein by htt – LC3 linker complexes Nature, 2019, DOI: 10.1038/s41586-019-1722-1 2 Potential entry points for Huntington's disease drug discovery https://mediaexpress.com/news/2019-10-potential-entry-huntington-disease-drug.html