The pathological origin of Alzheimer’s disease(AD)is still shrouded in mystery,despite intensive worldwide research efforts.The selective visualization ofβ-amyloid(Aβ),the most abundant proteinaceous deposit in AD,...The pathological origin of Alzheimer’s disease(AD)is still shrouded in mystery,despite intensive worldwide research efforts.The selective visualization ofβ-amyloid(Aβ),the most abundant proteinaceous deposit in AD,is pivotal to reveal AD pathology.To date,several small-molecule fluorophores for Aβspecies have been developed,with increasing binding affinities.In the current work,two organic small-molecule dioxaborine-derived fluorophores were rationally designed through tailoring the hydrophobicity with the aim to enhance the binding affinity for Aβ_(1-42) fibrils-while concurrently preventing poor aqueous solubility-via biannulate donor motifs in D-π-A dyes.An unprecedented sub-nanomolar affinity was found(K_(d)=0.62±0.33 nM)and applied to super-sensitive and red-emissive fluorescent staining of amyloid plaques in cortical brain tissue ex vivo.These fluorophores expand the dioxaborine-curcumin-based family of Aβ-sensitive fluorophores with a promising new imaging agent.展开更多
基金This research was supported by the National Research Foundation of Korea(CRI project no.2018R1A3B1052702,NRF-2019M3E5D1A01068998,J.S.Kim)the Korea University Graduate School Junior Fellow Research Grant(J.An)+3 种基金the National Research Council of Science&Technology(NST)granted by the Ministry of Science,ICT&Future Planning(MSIP)(No.CRC-15-04-KIST)the Korea Health Technology R&D Project through the Korea Health Industry Development Institute(KHIDI)and Korea Dementia Research Center(KDRC)the Ministry of Health&Welfare and Ministry of Science and ICT,Republic of Korea(No.HI20C1234)P.V.acknowledges support from Interne Fondsen KU Leuven/Internal Funds KU Leuven(STG/19/029).
文摘The pathological origin of Alzheimer’s disease(AD)is still shrouded in mystery,despite intensive worldwide research efforts.The selective visualization ofβ-amyloid(Aβ),the most abundant proteinaceous deposit in AD,is pivotal to reveal AD pathology.To date,several small-molecule fluorophores for Aβspecies have been developed,with increasing binding affinities.In the current work,two organic small-molecule dioxaborine-derived fluorophores were rationally designed through tailoring the hydrophobicity with the aim to enhance the binding affinity for Aβ_(1-42) fibrils-while concurrently preventing poor aqueous solubility-via biannulate donor motifs in D-π-A dyes.An unprecedented sub-nanomolar affinity was found(K_(d)=0.62±0.33 nM)and applied to super-sensitive and red-emissive fluorescent staining of amyloid plaques in cortical brain tissue ex vivo.These fluorophores expand the dioxaborine-curcumin-based family of Aβ-sensitive fluorophores with a promising new imaging agent.
