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Spastin and alsin protein interactome analyses begin to reveal key canonical pathways and suggest novel druggable targets

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Neural Regeneration research 2025年第3期20卷 725-739页

作者： Benjamin R.Helmold Angela Ahrens Zachary Fitzgerald P.Hande Ozdinler Department of Neurology Feinberg School of MedicineNorthwestern UniversityChicagoILUSA center for Molecular Innovation and drug discovery Center for Developmental TherapeuticsChemistry of Life Processes InstituteNorthwestern UniversityEvanstonILUSA Mesulam center for Cognitive Neurology and Alzheimer’s Disease Feinberg School of MedicineNorthwestern UniversityChicagoILUSA Feinberg School of Medicine Les Turner ALS Center at Northwestern UniversityChicagoILUSA

Developing effective and long-term treatment strategies for rare and complex neurodegenerative diseases is challenging. One of the major roadblocks is the extensive heterogeneity among patients. This hinders understanding the underlying disease-causing mechanisms and building solutions that have implications for a broad spectrum of patients. One potential solution is to develop personalized medicine approaches based on strategies that target the most prevalent cellular events that are perturbed in patients. Especially in patients with a known genetic mutation, it may be possible to understand how these mutations contribute to problems that lead to neurodegeneration. Protein–protein interaction analyses offer great advantages for revealing how proteins interact, which cellular events are primarily involved in these interactions, and how they become affected when key genes are mutated in patients. This line of investigation also suggests novel druggable targets for patients with different mutations. Here, we focus on alsin and spastin, two proteins that are identified as “causative” for amyotrophic lateral sclerosis and hereditary spastic paraplegia, respectively, when mutated. Our review analyzes the protein interactome for alsin and spastin, the canonical pathways that are primarily important for each protein domain, as well as compounds that are either Food and drug Administration–approved or are in active clinical trials concerning the affected cellular pathways. This line of research begins to pave the way for personalized medicine approaches that are desperately needed for rare neurodegenerative diseases that are complex and heterogeneous.

关键词： ALS2 alsin amyotrophic lateral sclerosis hereditary spastic paraplegia neurodegenerative diseases personalized medicine precision medicine protein interactome protein-protein interactions SPAST spastin

STING agonist-boosted mRNA immunization via intelligent design of nanovaccines for enhancing cancer immunotherapy

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National Science Review 2023年第10期10卷 123-138页

作者： Lei Zhou Wenzhe Yi Zehong Zhang Xiaoting Shan Zitong Zhao Xiangshi Sun Jue Wang Hao Wang Hualiang Jiang Mingyue Zheng Dangge Wang Yaping Li State Key Laboratory of drug research & center of Pharmaceutics Shanghai Institute of Materia MedicaChinese Academy of Sciences China State Institute of Pharmaceutical Industry Univerisity of Chinese Academy of Sciences drug discovery and Design center State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Precision research center for Refractory Diseases Shanghai General HospitalShanghai Jiao Tong University School of Medicine Shandong Laboratory of Yantai drug discovery Bohai Rim Advanced Research Institute for Drug Discovery

Messenger RNA(mRNA) vaccine is revolutionizing the methodology of immunization in ***,mRNA immunization is drastically limited by multistage biological barriers including poor lymphatic transport,rapid clearance,catalytic hydrolysis,insufficient cellular entry and endosome ***,we design a mRNA nanovaccine based on intelligent design to overcome these *** efficient nanovaccines are carried out with machine learning techniques from datasets of various nanocarriers,ensuring successful delivery of mRNA antigen and cyclic guanosine monophosphate-adenosine monophosphate(cGAMP) to *** activates stimulator of interferon genes(STING),promotes mRNA-encoded antigen presentation and boosts antitumour immunity in vivo,thus inhibiting tumour growth and ensuring long-term survival of tumour-bearing *** work provides a feasible and safe strategy to facilitate STING agonist-synergized mRNA immunization,with great translational potential for enhancing cancer immunotherapy.

关键词： vaccine mRNA STING cancer immunotherapy nanoparticles

Structure-based drug design of a novel family of chalcones as PPARα agonists:virtual screening,synthesis,and biological activities in vitro

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Acta Pharmacologica Sinica 2007年第12期28卷 2040-2052页

作者： Xiang-hua LI~(2,3),Han-jun ZOU~(2,3),An-hui WU~2,Yang-liang YE~2,Jian-hua SHEN~(2,4)~2 drug discovery and Design center,State Key Laboratory of drug research,Shanghai Institute of Materia Medica,Chinese Academy ofSciences,Shanghai 201203,China drug discovery and Design center State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai China

Aim:To design and synthesize a novel class of peroxisome proliferator-activatedreceptors (PPAR)α agonists,which is obtained by the combination of the classi-cal fibrate"head group",a linker with appropriate length and a ***:Thirty seven compounds were designed and identified employing the virtualscreening *** compounds were then selected for synthesis and bioas-say according to the virtual screening results,structural similarity,and ***:Six new compounds (4b and 4d-h) were synthesized *** were found to be potent PPARα agonists,compound 4 h being themost prominent with a 50% effective concentration value of 0.06 μmol/***:This study provides a promising novel family of chalcones with a potentialhypolipidemic effect.

关键词： peroxisome proliferator-activated receptors drug design virtual screening

The disruption of protein-protein interactions with co-chaperones and client substrates as a strategy towards Hsp90 inhibition

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Acta Pharmaceutica Sinica B 2021年第6期11卷 1446-1468页

作者： Michael A.Serwetnyk Brian S.J.Blagg Department of Chemistry and Biochemistry Warren Family Research Center for Drug Discovery and DevelopmentUniversity of Notre DameIN 46556USA

The 90-kilo Dalton(kD) heat shock protein(Hsp90) is a ubiquitous,ATP-dependent molecular chaperone whose primary function is to ensure the proper folding of several hundred client protein *** many of these clients are overexpressed or become mutated during cancer progression,Hsp90 inhibition has been pursued as a potential strategy for cancer as one can target multiple oncoproteins and signaling pathways *** first discovered Hsp90 inhibitors,geldanamycin and radicicol,function by competitively binding to Hsp90’s N-terminal binding site and inhibiting its ATPase ***,most of these N-terminal inhibitors exhibited detrimental activities during clinical evaluation due to induction of the pro-survival heat shock response as well as poor selectivity amongst the four ***,alternative approaches to Hsp90 inhibition have been pursued and include C-terminal inhibition,isoform-selective inhibition,and the disruption of Hsp90 protein-protein *** the Hsp90 protein folding cycle requires the assembly of Hsp90 into a large heteroprotein complex,along with various co-chaperones and immunophilins,the development of small molecules that prevent assembly of the complex offers an alternative method of Hsp90 inhibition.

关键词： Hsp90 Protein-protein interactions Disruptors Natural products Small molecules Peptidomimetics

Synthesis and biological evaluation of tetrahydroisoquinoline derivatives as potential multidrug resistance reversal agents in cancer

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Chinese Chemical Letters 2008年第2期19卷 169-171页

作者： Yu Li Hui Bin Zhang Wen Long Huang Xia Zhen Yun Man Li center of drug discovery China Pharmaceutical University Nanjing 210009 China

Tetrahydroisoquinoline derivatives were synthesized and their multidrug resistance reversal activities were evaluated in vitro. The results showed that some of the synthetic compounds had higher multidrug resistance ... 详细信息

关键词： Tetrahydroisoquinoline derivatives Synthesis Mulfidrug resistance (MDR) Peptoids

Potential applications of lactic acid bacteria and bacteriocins in antimycobacterial therapy

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Asian Pacific Journal of Tropical Medicine 2018年第8期11卷 453-459页

作者： Anbarasu Sivaraj Revathy Sundar Radhakrishnan Manikkam Krupakar Parthasarathy Uma Rani Vanaja Kumar Centre for drug discovery and Development Sathyabama Institute of Science and Technology

Tuberculosis(TB) is a communicable disease caused by Mycobacterium tuberculosis(M. tuberculosis). WHO estimated that 10.4 million new(incident) TB cases worldwide in year 2016. The increased prevalence of drug resistant strains and side effects associated with the current anti-tubercular drugs make the treatment options more complicated. Hence, there are necessities to identify new drug candidates to fight against various sub-populations of M. tuberculosis with less or no toxicity/side effects and shorter treatment duration. Bacteriocins produced by lactic acid bacteria(LAB) attract attention of researchers because of its "Generally recognized as safe" status. LAB and its bacteriocins possess an effective antimicrobial activity against various bacteria and fungi. Interestingly bacteriocins such as nisin and lacticin 3147 have shown antimycobacterial activity in vitro. As probiotics, LAB plays a vital role in promoting various health benefits including ability to modulate immune response against various infectious diseases. LAB and its metabolic products activate immune system and thereby limiting the M. tuberculosis pathogenesis. The protein and peptide engineering techniques paved the ways to obtain hybrid bacteriocin derivatives from the known peptide sequence of existing bacteriocin. In this review, we focus on the antimycobacterial property and immunomodulatory role of LAB and its metabolic products. Techniques for large scale synthesis of potential bacteriocin with multifunctional activity and enhanced stability are also discussed.

关键词： Bacteriocin Lactic acid bacteria Antimycobacterial peptides Tuberculosis Immunomodulation Hybrid bacteriocin

Nitric oxide donating anti-glaucoma drugs:advances and prospects

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Chinese Journal of Natural Medicines 2020年第4期18卷 275-283页

作者： MAO Yu-Jie WU Jian-Bing YANG Ze-Qiu ZHANG Yi-Hua HUANG Zhang-Jian State Key Laboratory of Natural Medicines Jiangsu Key Laboratory of Drug Discovery for Metabolic DiseasesCenter of Drug DiscoveryChina Pharmaceutical UniversityNanjing 210009China

Glaucoma is a disease that causes irreversible blindness. Reducing intraocular pressure(IOP) is the main treatment at present. Nitric oxide(NO), an endogenous gas signaling molecule, can increase aqueous humor outflow facility, inhibit aqueous humor production thereby reducing IOP, as well as regulate eye blood flow and protect the optic nerve. Therefore, NO donating antiglaucoma drugs have broad research prospects. In this review, we summarize NO-mediated therapy for glaucoma, and the state of the art of some NO donating molecules, including latanoprostene bunod in market and some other candidate compounds, for the intervention of glaucoma, as well as prospects and challenges ahead in this field.

关键词： Nitric oxide Glaucoma Intraocular pressure Trabecular meshwork Prostaglandin analogues

Design, synthesis, and biological evaluation of ligustrazine/resveratrol hybrids as potential anti-ischemic stroke agents

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Chinese Journal of Natural Medicines 2020年第8期18卷 633-640页

作者： ZHANG Yin-Qiu WU Jian-Bing YIN Wei ZHANG Yi-Hua HUANG Zhang-Jian State Key Laboratory of Natural Medicines Jiangsu Key Laboratory of Drug Discovery for Metabolic DiseasesCenter of Drug DiscoveryChina Pharmaceutical UniversityNanjing 210009China

To search for potent anti-ischemic stroke agents,a series of tetramethylpyrazine(TMP)/resveratrol(RES)hybrids 6 a-t were designed and *** hybrids inhibited adenosine diphosphate(ADP)-or arachidonic acid(AA)-induced platelet aggregation,among them,6 d,6 g-i,6 o and 6 q were more active than *** most active compound 6 h exhibited more potent antiplatelet aggregation activity than TMP,RES,as well as positive control ticlopidine(Ticlid)and aspirin(ASP).Furthermore,6 h exerted strong antioxidative activity in a dose-dependent manner in rat pheochromocytoma PC12 cells which were treated with hydrogen peroxide(H2 O2)or hydroxyl radical(·OH).Importantly,6 h significantly protected primary neuronal cells suffered from oxygen-glucose deprivation/reoxygenation(OGD/R)injury,comparable to an anti-ischemic drug edaravone(Eda).Together,our findings suggest that 6 h may be a promising candidate warranting further investigation for the intervention of ischemic stroke.

关键词： Ligustrazine Resveratrol Hybrids Anti-platelet aggregation Antioxidant Ischemic stroke

New glowing dyes in vivo imaging with wavelengths beyond 1500 nm

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Science China Chemistry 2019年第1期62卷 7-8页

作者： Jing Yang Xuechuan Hong State Key Laboratory of Virology Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (MOE) and Hubei Province Engineering and Technology Research Center for Fluorinated Pharmaceuticals Wuhan University School of Pharmaceutical Sciences

Near-infrared (NIR)fluorescence imaging in the second near-infrared region (NIR-H,1000-1700 nm)is an important and attractive imaging method for biomedical research and clinical applications,and can achieve high spatial resolution, high signal-to-background ratio (SBR)and deeper tissue imaging owing to nearly zero auto-fluorescence background and tissue scattering .Smaller optical sub-window such as NIR-IIb (1500-1700 nm)has provided significant improvements in in vivo fluorescence imaging clarity and penetration depth.

关键词： Near-infrared (NIR)fluorescence Smaller optical fluorescence