WuXi AppTec WuXi AppTec 2022-10-01 07:00 Posted in Shanghai Every successful clinical drug developed is the earliest of the efforts of scientists in the laboratory, and the first step is to identify suitable targets to develop corresponding therapeutic drugs.

2025/04/2316:47:39 regimen 1554

WuXi AppTec WuXi AppTec 2022-10-01 07:00 published in Shanghai

Behind every successful clinical drug developed is the first to come from the efforts of scientists in the laboratory, and the first step is to identify suitable targets to develop corresponding therapeutic drugs. In today's article, WuXi AppTec's content team will take stock of articles recently published in various top scientific journals and have the potential to become targets for the treatment of neuromuscular, gastrointestinal and other diseases, to provide reference for research and development in the industry!

Target: TMEM175

Disease: Parkinson’s disease (Parkinson’s disease)

Journal/PMID: " Cell "/ 35750034

found: lysosome relies on its V-adenosine triphosphatase (V-ATPase) function to cause proton inflow, and an undiscovered proton loss pathway to maintain the lysosome cavity PH value between 4.5-5.0 to effectively digest macromolecules in the cavity. The researchers found that TMEM175 can serve as a proton-activated cetonic proton-selective channel (LyPAP) on lysosomal membranes to mediate lysosomal proton loss. TMEM175 was previously considered a genetic risk factor for Parkinson's disease. Excessive acidification of lysosomes activates LyPAP, and an endogenous polyunsaturated fatty acid and synthetic agonists can also activate TMEM175 to release protons in lysosomes. The deletion of TMEM175 will cause excessive acidification of lysosomes and affect proteolysis, thereby promoting the aggregation of α synuclein (α-syncuclein) in the body. therefore has the potential to regulate lysosomal degradation and Parkinson's pathological progression by regulating the pH value of TMEM175 or lysosomal cavity.

Target: PRPF6

Disease: periventrical heterotopia (PH)

Journal/PMID: Science/ 35709258

found: centrosome (centrosome) is a linkage of cytoskeleton in the cell, regulating cell division, migration and cilia formation. The researchers analyzed the interaction network of neural stem cells (NSCs) from human -induced pluripotent stem cells and proteins on the centrosome through spatial proteomics . When analyzing the neurodevelopmental disease cohort, the researchers found that there were many variants in NSC centrosome proteins in patients with paraventricular ectopic . When researchers express the PRPF6 variant protein, they can replicate ventricular ectopic situations in the developing mouse brain. is involved in the splicing of mRNA precursors because PRPF6 is involved in splicing of mRNA precursors, which shows that missplicing of microtubule-associated kinase transcripts is necessary for the production of brain disease manifestations, and mutated PRPF6 may be a potential target.

Target: GAT3

Disease: Brain injury (brain injury)

Journal/PMID: Science Translational Medicine / 35857628

found that the uncontrollable inflammatory response caused by brain injury is related to the patient's risk of epilepsy and increased cognitive damage, and the thalamus in the brain is a part that is particularly susceptible to such damage after brain injury. The researchers found that in mouse models, opticum inflammation itself is sufficient to trigger negative effects caused by brain damage such as high irritation of cells and circuits and increased risk of epilepsy. This phenomenon is caused by downregulation of the GABA transporter GAT3 in astrocytes. and increasing the expression of GAT3 protein in the opticum astrocytes can reduce the risk of epilepsy, repair the cortical state, and protect epilepsy and death caused by severe chemical convulsants in the mouse brain injury model. Therefore, GAT3 expression may help reduce the negative effects of brain damage.

Target: ZBP1

Disease: Aicardi-Goutières syndrome (AGS)

Journal/PMID: 《Natural 》/ 35859175, 35859176

found: RNA1 adenosine deaminase (ADAR1) is an RNA editing enzyme that can limit the accumulation of endogenous immunostimulatory double-stranded RNA (dsRNA). The reduction of ADAR1 activity in humans can cause severe early onset and rare hereditary inflammatory disease - Ekadi-Guterres syndrome (AGS), which mainly affects the patient's brain and skin. The ADAR1 mutation in AGS patients will cause an autoinflammatory response in mice. was published in two papers in the same issue of Nature. It was found that ADAR1 can inhibit the levo Z-nucleic acid sensing protein ZBP1. ZBP1 can promote type 1 interferon (IFN) activation. In cells lacking ADAR1, ZBP1 causes caspase-8 (caspase-8)-dependent apoptosis and MLKL-mediated necrotic apoptosis. researchers found that the Zα domain of ADAR1 can promote A conversion to I base editing, avoiding the formation of double-stranded RNA (dsRNA) and subsequent activation of ZBP1 protein. Therefore, has the potential to treat ZBP1-mediated interferon pathes caused by ADAR1 mutation in AGS patients.

Target: HRH4

Disease: Irritable bowel syndrome (IBS)

Journal/PMID: Science Translational Medicine / 35895832

Discovery: Microorganisms in the intestine are one of the causes of chronic and painful intestinal discomfort including IBS, but the detailed mechanism is still unclear. The researchers found that histamine, a neuroimmune regulator, produced by gut bacteria, causes abdominal pain in a mouse model of IBS. Mechanistically, bacterial histamine can attract mast cells to the colon by activating histamine 4 receptor (HRH4), making it highly sensitive. A large number of bacteria containing this Klebsiella aerogenes4 in the feces of IBS patients were found in the feces of IBS, while inhibiting HRH4 with drugs can slow down the accumulation of mast cells in the colon and intestinal sensitivity of mice. thus lowering bacterial histamine or targeting the intestinal histamine 4 receptor may help improve IBS symptoms.

Target: RASAL1

Disease: peptic ulcer (peptic ulcer)

Journal/PMID: Science Translational Medicine / 35857828

Discovery: Peptid ulcer is a common clinical problem and may cause serious complications such as bleeding or perforation. The secretion of gastric acid is one of the decisive factors that cause peptic ulcers, and its secretion is controlled by gastrin produced by G cells in the stomach. The researchers found that axonal oriented protein (semaphorin) and plexin (plexin) signaling pathway can inhibit the secretion of gastrin in G cells, thereby limiting gastric acid secretion caused by food, and the Ras GTPase-activated protein RASAL1 is the central mediator of this signaling pathway. In addition, RASAL1 has also been found to be related to the course of disease caused by non-steroidal anti-inflammatory drugs (NSAIDs), the main risk factor for human peptic ulcers. Therefore, targeting RASAL1 drugs has the potential to inhibit gastric acid secretion and relieve peptic ulcers.

I hope these excellent research results can enter clinical transformation as soon as possible, bringing different treatment options and possible improvements in life quality to patients with various diseases!

Reference:

[1] Hu, Meiqin et al. (2022) Parkinson's disease-risk protein TMEM175 is a proton-activated proton channel in lysosomes. Cell 185,13: 2292-2308.e20. DOI:10.1016/j.cell.2022.05.021

[2] O'Neill, Adam C et al. (2002) Spatial Centrosome protein of human neural cells uncovers disease-relevant heterogeneity. Science 376,6599: eabf9088. DOI:10.1126/science.abf9088

[3] Cho, Frances S et al. (2022) Enhancing GAT-3 in thalamic astrocytes promotes resilience to brain injury in rodents. Science translational medicine 14,652: eabj4310. DOI:10.1126/scitranslmed.abj4310

[4] De Palma, Giada et al. (2022) Histamine production by the gut microbiota induces visceral hyperalgesia through histamine 4 receptor signaling in mice. Science translational medicine14,655: eabj1895. DOI:10.1126/scitranslmed.abj1895

[5] Xu, Rui et al. (2022) A semaphorin-plexin-Rasal1 signaling pathway inhibits gastrin expression and protects against peptic ulcers. Science translational medicine 14,654: eabf1922. DOI:10.1126/scitranslmed.abf1922

[6] de Reuver, Richard et al. (2022) ADAR1 prevents autoinflammation by suppressing spontaneous ZBP1 activation. Nature 607,7920: 784-789. DOI:10.1038/s41586-022-04974-w

[7] Jiao, Huipeng et al. (2022) ADAR1 averts fatal type I interferon induction by ZBP1. Nature 607,7920: 776-783. DOI:10.1038/s41586-022-04878-9

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