Investigation of targeting inhibitors of Aβ aggregation, heme-Aβ peroxidase-like activity and efficient detectors of Aβ aggregation, are of therapeutic value and diagnostics significance for the treatment of Alzheimer's disease (AD). Due to the complex pathogenesis of AD, theranostics treatment with multiple functions are necessary. Herein we constructed the NIR absorption property of gold nanorods (GNRs) loaded with single chain variable fragment ( scFv ) 12B4 and thermophilic acylpeptide hydrolase (APH) ST0779 as a smart theranostic complex (GNRs-APH- scFv , GAS), which possesses both rapid detection of Aβ aggregates and NIR photothermal treatment that effectively disassembles Aβ aggregates and inhibits Aβ-mediated toxicity. Methods : We screened targeting anti-Aβ scFv 12B4 and thermophilic acylpeptide hydrolase as amyloid-degrading enzyme, synthesized GAS gold nanorods complex. The GAS was evalued by Aβ inhibition and disaggregation assays, Aβ detection assays, Aβ mediated toxicity assays in vitro . In vivo, delaying Aβ-induced paralysis in AD model of Caenorhabditis elegans was also tested by GAS. Results : In vitro , GAS has a synergistic effect to inhibit and disassociate Aβ aggregates, in addition to decrease heme-Aβ peroxidase-like activity. In cultured cells, treatment with GAS reduces Aβ-induced cytotoxicity, while also delaying Aβ-mediated paralysis in CL4176 C.elegans model of AD. Furthermore, the photothermal effect of the GAS upon NIR laser irradiation not only helps disassociate the Aβ aggregates but also boosts APH activity to clear Aβ. The GAS, as a targeting detector and inhibitor, allows real-time detection of Aβ aggregates. Conclusion : These results firstly highlight the combination of scFv , APH and nanoparticles to be theranostic AD drugs. Taken together, our strategy provides a new thought into the design of smart compounds for use as efficiently therapeutic and preventive agents against AD. Moreover, our design provides broad prospects of biomedical strategy for further theranostics application in those diseases caused by abnormal protein.
Influenza viruses are a major public health threat worldwide. The influenza hemagglutinin (HA) plays an essential role in the virus life cycle. Due to the high conservation of the HA stem region, it has become an especially attractive target for inhibitors for therapeutics. In this study, molecular simulation was applied to study the mechanism of a small molecule inhibitor (MBX2329) of influenza HA. Behaviors of the small molecule under neutral and acidic conditions were investigated, and an interesting dynamic binding mechanism was found. The results suggested that the binding of the inhibitor with HA under neutral conditions facilitates only its intake, while it interacts with HA under acidic conditions using a different mechanism at a new binding site. After a series of experiments, we believe that binding of the inhibitor can prevent the release of HA1 from HA2, further maintaining the rigidity of the HA2 loop and stabilizing the distance between the long helix and short helices. The investigated residues in the new binding site show high conservation, implying that the new binding pocket has the potential to be an effective drug target. The results of this study will provide a theoretical basis for the mechanism of new influenza virus inhibitors.Influenza virus is the causative agent of influenza, an infectious disease which usually leads to symptoms such as high fever, cough, headache, muscle and joint pain, sore throat, nasal discharge, and even a fatal illness similar to pneumonia 1-4 . Influenza viruses are divided into three types, type A, type B and type C, with influenza A virus presenting serious threats to public health worldwide due to its high mutation rate [5][6][7] . At present, two classes of drugs are approved by the Food and Drug Administration for treatment or chemoprophylaxis of influenza: matrix protein 2 (M2) inhibitors amantadine and rimantadine and the neuraminidase (NA) inhibitors (NAIs) oseltamivir and zanamivir 8,9 . However, with the wide use of these drugs, drug-resistant strains have appeared in succession 10 . Therefore, new antiviral targets with novel inhibition mechanism need to be developed.Hemagglutinin (HA), a viral receptor-binding and membrane-fusion glycoprotein involved in the invasion of influenza into host cells, plays an essential role in the life cycle of influenza A virus 3,11 . HA is a trimer of identical subunits, each of which consists of a variable membrane-distal receptor-binding globular domain (HA1) and a more conserved membrane-proximal helix-rich stem structure (HA2) 12 . Under acidic conditions, the residues on the outer surface of HA1 can be protonated easily, which leads to the large gathering of positive charges on the surface of HA 13,14 . With gradually increased charges, disaggregation of HA first occurs as the positive charges repel each other, followed by the entry of water into the interior of the protein causing further structural changes of HA2 13 . In the HA2 subunit, one short and one long α-helical segment are connected by a loop (helix-loo...
The ectodomain of the influenza A virus (IAV) hemagglutinin (HA) stem is highly conserved across strains and has shown promise as a universal influenza vaccine in a mouse model. In this study, potential B-cell epitopes were found through sequence alignment and epitope prediction in a stem fragment, HA2:90-105, which is highly conserved among virus subtypes H1, H3 and B. A norovirus (NoV) P particle platform was used to express the HA2:90-105 sequences from subtypes H1, H3 and B in loops 1, 2 and 3 of the protrusion (P) domain, respectively. Through mouse immunization and microneutralization assays, the immunogenicity and protective efficacy of the chimeric NoV P particle (trivalent HA2-PP) were tested against infection with three subtypes (H1N1, H3N2 and B) of IAV in Madin–Darby canine kidney cells. The protective efficacy of the trivalent HA2-PP was also evaluated preliminarily in vivo by virus challenge in the mouse model. The trivalent HA2-PP immunogen induced significant IgG antibody responses, which could be enhanced by a virus booster vaccination. Moreover, the trivalent HA2-PP immunogen also demonstrated in vitro neutralization of the H3 and B viruses, and in vivo protection against the H3 virus. Our results support the notion that a broadly protective vaccine approach using an HA2-based NoV P particle platform can provide cross-protection against challenge viruses of different IAV subtypes. The efficacy of the immunogen should be further enhanced for practicality, and a better understanding of the protective immune mechanism will be critical for the development of HA2-based multivalent vaccines.
Latest studies suggest that Alzheimer's disease (AD) is one of the "four big killers" that threaten the health of the elderly. AD affects about 46 million people across the world, and there is a critical need for research on new therapies for treating AD. The purpose of the present study was to develop and evaluate immunogens to elicit antibodies against the formation of amyloid beta protein (Aβ), a pathological hallmark of AD, as a therapeutic strategy in AD. In this study, serial potential immunogenic epitopes were screened according to the Aβ sequence. The screened linear epitopes on the Aβ C-terminal fragment were coupled with either the carrier protein keyhole limpet hemocyanin (KLH) or the synthesized 4-branch peptide (MAP 4 ). MAP 4 immunogens could effectively elicit immunogenicity against Aβ 1−42 monomer and fiber in Balb/C mice. Furthermore, MAP 4 sera could also effectively inhibit the formation of the Aβ 1−42 fiber. Interestingly, one of the MAP 4 sera was able to depolymerize the Aβ 1−42 fibers that had aggregated. The monoclonal antibody, 1H7, was shown to inhibit the formation of Aβ 1−42 fiber. MAP 4 carrier may provide benefits over current immunization strategies, as it does not induce inflammation. In conclusion, the MAP 4 -Aβ conjugates offer a promising approach for the development of a safe and effective AD vaccine.
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