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Targeting AbcA1 and Ldlr production for the Discoveryof Alzheimer's disease Drugs

靶向 AbcA1 和 Ldlr 的产生以发现阿尔茨海默病药物

基本信息

批准号：
10612951
负责人：
Santanu Maitra
金额：
$ 13.98万
依托单位：
CALIFORNIA STATE UNIVERSITY FRESNO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10612951
关键词：
ATP binding cassette transporter 1 ATP-Binding Cassette Transporters Affect Aging Alzheimer&apos s Disease Amines Amyloid Apolipoprotein E Apolipoproteins Astrocytoma Biological Blood - brain barrier anatomy Brain Carrier Proteins Cell Line Chemicals Cholesterol Dementia Deposition Drug Kinetics Endocytosis Enzyme-Linked Immunosorbent Assay Future Genes Goals Grant Human In Vitro Individual Laboratories Lead Libraries Link Lipids Low Density Lipoprotein Receptor Modification Mus Pathogenesis Pharmaceutical Preparations Phase Play Process Production Protein Isoforms Proteins Research Role Senile Plaques Structure-Activity Relationship Student recruitment Students Sulfonamides Therapeutic Toxicology Training Transgenic Mice Underrepresented Students Western Blotting amyloid formation amyloid pathology analog antagonist apolipoprotein E-3 apolipoprotein E-4 appendage brain cell career chemical synthesis experimental study extracellular genetic risk factor higher education in vivo lipophilicity medical schools molecular mass nervous system disorder novel overexpression pharmacophore recruit replication factor C scaffold screening small molecule undergraduate student

项目摘要

Alzheimer’s disease is the most common incurable form of dementia affecting 50 million individuals worldwide. Apolipoprotein E4 (APOE4) is the strongest genetic risk factor that is directly linked to its pathogenesis. ApoE is a cholesterol- and lipid-carrier protein that has been implicated in Alzheimer’s disease, aging, and other neurological disorders. Isoform-dependent effect on amyloid accumulation and clearance have been found in humans and mice with APOE4 being detrimental. Haploinsufficiency of ApoE4 and possibly ApoE3 decreases amyloid pathology. Low Density Lipoprotein Receptor (LDLR) plays an important role in the endocytosis of ApoE proteins. LDLR overexpression has been found to decrease ApoE levels and inhibit amyloid formation. Additionally, ApoE’s role in lipidation influences Alzheimer’s pathogenesis. ATP-binding cassette transporter A1 (AbcA1) protein transfers cellular cholesterol onto extracellular lipid-poor apolipoproteins. Overexpression of ABCA1 gene has also been found to inhibit amyloid formation. Therefore, we set out to develop small organic molecules that can increase AbcA1 and/or Ldlr while decreasing ApoE protein levels. Such compounds would likely reduce and clear amyloid plaque deposition in affected brains and provide therapeutic benefit in Alzheimer’s disease. Five triarylmethyl amine (TAMA) small molecules emerged as first leads decreasing ApoE protein level (>30% reduction in the human astrocytoma brain cell line, analyzed using ELISA). The mechanism of action of the TAMA pharmacophore was via LXR antagonism. Structure-Activity Relationship (SAR) studies on the TAMA pharmacophore in five phases of focused libraries, identified five drug-like tertiaryl sulfonamides and aryl amines as new leads. They not only decreased ApoE levels in vitro, but also increased AbcA1/Ldlr protein levels validated by concentration-dependent studies. Three chiral leads in pure R/S forms had disproportionate effects on ApoE and AbcA1 raising the possibility of multiple targets. One of the 8 leads, compound 127 modulated the target proteins in the transgenic mice brains in preliminary in vivo studies. The successful in vivo efficacy of 127 validates its ability to pass the blood-brain barrier (BBB). Preliminary in vitro toxicological experiments revealed all the 8 lead compounds to be not toxic. The SuRE support will enable PI and his undergraduate/graduate research team to utilize the TAMA pharmacophore with critical appendages identified in newer and more potent sulfonamide leads to generate new and novel scaffolds-based leads. These scaffolds are expected to be lighter, drug-like, chemically and pharmacokinetically stable, and less lipophilic. PI aims at performing chemical synthesis and biological screening in his lab with the guidance of a committed consultant.

阿尔茨海默病是最常见的无法治愈的痴呆症，影响着5000万人