Design Of β-Amyloid Inhibitors And Facilitation Of Nanomotor On Inhibitory Effects

The abnormal formation of toxic aggregates from amyloid-βprotein（Aβ）is a major pathological hallmark of Alzheimer’s disease（AD）.Therefore,the design of novel Aβinhibitors plays a critical role in AD therapy.Based on the design principles of different Aβinhibitors,we constructed and synthesized three novel inhibitors including peptide,nanomotor,and nanocluster for modulating Aβaggregation,rescuing cell from Aβ-induced cytotoxicity.According to chiral selectivity of Aβinhibitors,we designed a multifunctional D-decapeptide（D-RK10）,and the effects of chirality on Aβfibrillogenesis,reactive oxygen species（ROS）suppression,Cu²⁺-mediated Aβaggregation,and aggregate-remodeling effects were systematically investigated.The results revealed the higher inhibitory potency of D-RK10 than L-RK10 on Aβfibrillogenesis.At an equimolar concentration to Aβ,L-RK10 and D-RK10 increased the cell viability from60±2%to 71±3%and 91±3%,respectively.Although the two enantiomers possessed similar properties on Cu²⁺chelation,ROS inhibition,and oxidative damage rescue,it was the D-enantiomer that showed enhanced suppression on Cu²⁺-induced Aβaggregation.Both enantiomers could remodel mature Aβ-Cu²⁺aggregates by Cu²⁺chelation,and D-RK10 exhibited higher remodeling performance and could protect the disrupted species from reaggregation.This research indicated that chiral derivatization of multifunctional peptide inhibitors is an effective strategy to enhance the inhibitory potency.Inspired by nanomotor-enhanced chemical process,by conjugating the above-designed decapeptide D-RK10,we constructed an inhibitor-functionalized near infrared（NIR）laser-powered Janus nanomotor（JNM-I）and first applied for modulating Aβaggregation.Under NIR laser irradiation,JNM-I exhibited significant propulsion through the“self-thermophoretic”effect,and the active motion of JNM-I increased the opportunity of the contacts between the inhibitors and Aβspecies,facilitating the inhibition of Aβfibrillogenesis.Furthermore,NIR irradiation enhanced the blood-brain barrier penetration of JNM-I.The proposal of using artificial nanomotors to facilitate modulation of Aβaggregation has provided new insights into the design of inhibitors.Based on the modulation of Aβaggregation through photooxygenation,we synthesized photooxidative gold nanocluster（Au NCs@HSA）using Aβ-affinity human serum albumins（HSA）as template,and further modified with ethylene diamine to create basified HSA-gold nanocluster composites（Au NCs@HSA-B）.The Au NCs@HSA-B showed stronger inhibition potency than Au NCs@HSA.Under NIR light,the produced single oxygen（¹O₂）by photodynamic processes can oxygenate Aβmonomers,resulting in inhibiting Aβfibrillogenesis and extending the longevity of transgenic Caenorhabditis elegans CL2006.To sum up,three novel Aβmodulators were designed by the chiral derivatization of peptide,the intensification of nanomotor,and the photooxygenation of photosensitizing agent.We believe this research would provide potential drug candidates and therapeutic strategies for the prevention and treatment of AD.