Cyclic Form Research Articles

Disrupted de novo pyrimidine biosynthesis impairs adult hippocampal neurogenesis and cognition in pyridoxine-dependent epilepsy.

Despite seizure control by early high-dose pyridoxine (vitamin B6) treatment, at least 75% of pyridoxine-dependent epilepsy (PDE) patients with ALDH7A1 mutation still suffer from intellectual disability. It points to a need for additional therapeutic interventions for PDE beyond pyridoxine treatment, which provokes us to investigate the mechanisms underlying the impairment of brain hemostasis by ALDH7A1 deficiency. In this study, we show that ALDH7A1-deficient mice with seizure control exhibit altered adult hippocampal neurogenesis and impaired cognitive functions. Mechanistically, ALDH7A1 deficiency leads to the accumulation of toxic lysine catabolism intermediates, α-aminoadipic-δ-semialdehyde and its cyclic form, δ-1-piperideine-6-carboxylate, which in turn impair de novo pyrimidine biosynthesis and inhibit NSC proliferation and differentiation. Notably, supplementation of pyrimidines rescues abnormal neurogenesis and cognitive impairment in ALDH7A1-deficient adult mice. Therefore, our findings not only define the important role of ALDH7A1 in the regulation of adult hippocampal neurogenesis but also provide a potential therapeutic intervention to ameliorate the defective mental capacities in PDE patients with seizure control.

Conformational Effects on the Absorption Spectra of Phytochromes.

Bacteriophytochrome is a photoreceptor protein that contains the biliverdin (BV) chromophore as its active component. The spectra of BV upon mutation remain remarkably unchanged, as far as spectral positions are concerned. This points toward the minimal effect of electrostatic effects on the electronic structure of the chromophore. However, the relative intensities of the Q and Soret bands of the chromophore change dramatically upon mutation. In this work, we delve into the molecular origin of this unusual intensity modulation. Using extensive classical MD and QM/MM calculations, we show that due to mutation, the conformational population of the chromophore changes significantly. The noncovalent interactions, especially the stacking interactions, lead to extra stabilization of the cyclic form in the D207H mutated species as opposed to the open form in the wild-type BV. Thus, unlike the commonly observed direct electrostatic effect on the spectral shift, in the case of BV the difference observed is in varying intensities, and this in turn is driven by a conformational shift due to enhanced stacking interaction.

Restraining Staphylococcus aureus Virulence Factors and Quorum Sensing through Lactic Acid Bacteria Supernatant Extracts

The escalating prevalence of antibiotic-resistant bacteria poses a grave threat to human health, necessitating the exploration of novel alternatives to conventional antibiotics. This study investigated the impact of extracts derived from the supernatant of four lactic acid bacteria strains on factors contributing to the pathogenicity of three Staphylococcus aureus strains. The study evaluated the influence of lactic acid bacteria supernatant extracts on the growth, biofilm biomass formation, biofilm metabolic activity, and biofilm integrity of the S. aureus strains. Additionally, the impact on virulence factors (hemolysin and coagulase) was examined. Gas chromatography coupled with mass spectrometry was used to identify the bioactive compounds in the extracts, while molecular docking analyses explored potential interactions. Predominantly, the extracts contain eight 2,5-diketopiperazines, which are cyclic forms of peptides. The extracts demonstrated inhibitory effects on biofilm formation, the ability to disrupt mature biofilms, and reduce the biofilm cell metabolic activity of the S. aureus strains. Furthermore, they exhibited the ability to inhibit α-hemolysin production and reduce coagulase activity. An in silico docking analysis reveals promising interactions between 2,5-diketopiperazines and key proteins (SarA and AgrA) in S. aureus, confirming their antivirulence and antibiofilm activities. These findings suggest that 2,5-diketopiperazines could serve as a promising lead compound in the fight against antibiotic-resistant S. aureus.

Abstract 5923: Innovative cyclic peptide disrupts IL-17RB/MLK4 Interaction for targeted pancreatic cancer therapy

Abstract Interleukin-17B (IL-17B) and its receptor IL-17RB drive oncogenic signaling in pancreatic cancer by interacting with mixed-lineage kinase 4 (MLK4) and phosphorylating IL-17RB's tyrosine-447 site. Our study highlights a therapeutic peptide (amino acids 403-416 of IL-17RB) that disrupts MLK4 binding. Improving its efficacy, we transformed the linear peptide into a disulfide-bonded cyclic form, exhibiting enhanced uptake and stability. The modified cyclic peptide outperformed the linear counterpart, effectively inhibiting the growth and metastasis of PDAC tumor cells in vitro and in a mouse model. Molecularly, we identified the critical role of cysteine (C) residue C408 in IL-17RB, mediating interaction with arginine (R)216 in MLK4's kinase domain. This interaction is pivotal for the cyclic peptide's efficacy. Additionally, lysine (K) residue K410 in IL-17RB maintains the cyclic peptide's structural integrity. These findings provide a comprehensive molecular understanding of IL-17RB and MLK4 interaction, offering innovative strategies for designing therapeutic molecules against pancreatic cancer. Citation Format: Yung-Chen Lo, YL Ko, CH Huang, JH Lee, DN Wu, YT Wu, HM Yu, Cn-Mei hu. Innovative cyclic peptide disrupts IL-17RB/MLK4 Interaction for targeted pancreatic cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5923.

Safety profile of ZnO active packaging PBAT based biomaterial for food packaging. First tier evaluation

Materials produced with polybutylene adipate terephthalate (PBAT) and starch are raising great interest for packaging and food contact applications, including as support for active antimicrobial agents such as zinc oxide nanoparticles (ZnO). Studies focusing on the safety of these materials as evaluated with the current reference rules for food contact materials, are lacking. A commercially available PBAT/starch-based material was incorporated with ZnO and the overall and specific migration of the films were studied at different conditions of simulants and temperature. The overall migration (OM) limit is exceeded due to the release of starch as confirmed by infrared spectroscopy. The impact of temperature on the OM was higher for the ethanol 10%. The incorporation of ZnO particles reduced the OM, for both temperatures tested for ethanol 10%. The impact of incorporating ZnO in the migration into acetic acid was relevant at 20 °C only. Beside starch, most relevant migrants were PBAT oligomers made of butanediol and two different kinds of diacids, terephthalic acid or adipic acid. The cyclic diester of 1,4-butanediol and adipic acid, butenyl butanediol adipate in either cyclic and linear form and oligomers terephthalic acid, but-3-enyl hexadecyl ester were detected in an untargeted screening with GC-MS. A second TPA oligomer was not fully identified. The specific migration was in several cases, depending on the simulant and on the temperature, higher than 50 μgkg−1 (semi-quantification), the threshold value for requiring additional toxicity test (genotoxicity tests applied to oligomers below 1000 Da). This indicates the need for more detailed studies with more precise quantification to verify the need for toxicity tests.

Harnessing Endogenous Peptide Compounds as Potential Therapeutics for Severe Influenza

Abstract Background Excessive pulmonary inflammation and damage are characteristic features of severe influenza virus infections. LAT8881 is a synthetic 16–amino acid cyclic peptide form of a naturally occurring C-terminal fragment of human growth hormone with therapeutic efficacy against influenza. Shorter linear peptides are typically easier to manufacture and formulate for delivery than larger cyclic peptides. A 6–amino acid linear peptide fragment of LAT8881, LAT9997, was investigated as a potential influenza therapy. Methods LAT9997 was evaluated for its potential to limit disease in a preclinical mouse model of severe influenza infection. Results Intranasal treatment of mice with either LAT8881 or LAT9997 from day 1 following influenza infection significantly improved survival outcomes. Initiating LAT9997 treatment at the onset of severe disease also significantly improved disease severity. Greater disease resistance in LAT9997-treated mice correlated with reduced lung immunopathology, damage markers, vascular leak, and epithelial cell death. Treatment reduced viral loads, cytokines, and neutrophil infiltration in the airways yet maintained protective alveolar macrophages in a dose-dependent manner. Sequential trimming of N- and C-terminal amino acids from LAT9997 revealed a structure-activity relationship. Conclusions These findings provide preclinical evidence that therapeutic LAT9997 treatment limits viral burden and characteristic features of severe influenza, including hyperinflammation and lung damage.

A DFT study of electronic structure, magnetic properties and cyclization reaction of [5]helicene derivatives

A series of 1,14-dimethyl-[5]helicene derivatives comprising radicals ((2,2,6,6-tetramethylpiperidin-1-yl)oxyl, 1,2,3,5-dithiadiazolyl, 1,5-dimethyl-6-oxo-verdazyl and 4,4,5,5-tetramethyl-4,5-dihydro-1H-imidazol-1-oxyl-3-oxide) was investigated by quantum-chemical modeling of their electronic structure, exchange interactions and cyclization reaction. The performed DFT study of 1,14-dimethyl-[5]helicene, supported by DFT/CASSCF and DFT/NEVPT2 calculations, have shown that cyclic form of this compound represents a singlet biradical. The energy barriers of transition between open and cyclic forms of 1,14-dimethyl-[5]helicene radical derivatives are comparable to the values characteristic of enantiomerization reaction, which indicates a high probability of formation of cyclic isomers under thermal conditions. The TD DFT calculations of electronic transitions predicted the presence of non-overlapping bands in the studied isomers that favors switching between them by irradiation. The variation in a number of paramagnetic centers as a result of interconversion of open and cyclic forms, and the presence of structures bearing strong ferromagnetic exchange interactions, make the considered [5]helicene derivatives a suitable basis for molecular electronics devices.

FT-IR measurement as a simple tool for following formation of acidic functional groups in maleic anhydride containing polymers

Titration is a measurement for maleic-anhydride containing polymers with significant chemicals consumption, time and human resource requirement meanwhile all the carbonyl groups have to be supposed to be in the cyclic form but it is not always the situation. Core of the FT-IR method has been determination of carbonyl groups in various chemical environments. The FT-IR method is developed to obtain more precise and prompt results about anhydride rings in the copolymer chain than with titration in the whole coupling number range with minimal chemicals consumption. Quantitatively apprising FT-IR results peaks of carbonyl groups have been considered since those yield well-isolated and high intensity peaks in the spectrum. Two distinct methods have been adopted for integration of areas under the selected stretching vibrations. Not all the anhydrides have been supposed to be in ring form in the copolymers but partially in acidic form that can be only taken into account by double counting during titration instead of the correctly single counting. FT-IR spectrum has been feasible for tracing that progress but titration isn't.Moreover, if difference between acid number from titration and FT-IR methods based on the chemical structure is high compatibilizing additive synthesis requires excess of reagents.•A method enabling the identification of carbonyl groups in maleic-anhydride containing polymers in various chemical environment without chemical consumption.•The method is based on the calculation of functional group ratios applying the integrated area of selected absorption peaks.

DFT Model of Elemental Sulfur in Sulfolane Solutions.

The structure and the thermodynamic and optical (UV) properties of elemental sulfur solution in sulfolane (Sl) have been studied using density functional theory methods. The cyclic molecular form of sulfur (S8 "crown") was found using PBE1PBE/6-311+G(d,p) approximation in combination with a polarizable continuum model (the integral equation formalism variant) to exist in sulfolane medium as a Sl-S8-Sl solvate. It has been theoretically established that sulfur can form stable (S8)n clusters in concentrated solutions. An increase in the extent of association (n) of the sulfur cluster leads to a decrease in the extinction coefficient [TD-DFT(TPSSTPSS/6-311+G(d,p))] of the most intense absorption maximum lying at about 50,000 cm-1 while maintaining the shape of the remaining part of the spectrum. The observed pattern qualitatively expresses the spectral regularities of solutions with different concentrations of sulfur in sulfolane. It has been proposed that a model of the absorption spectrum of elemental sulfur suggests a minor contribution of the S12 molecular form (G298°((S12)2) - G298°((S8)3) ≈ -15.5 kJ mol-1). The findings of the study will provide deeper insights into the transformation of molecular forms of sulfur and more precisely analyze processes involving sulfur as an acting species using electronic spectroscopy.

Kinetics of direct and water‐mediated tautomerization reactions of nucleobases at low temperatures ⩽200 K

AbstractDetailed chemical kinetic mechanisms for the synthesis of complex organic molecules in the interstellar medium are at an early stage of developement. That such synthesis must take place is well‐known from chemical analysis of sampled asteroids. As molecular complexity increases the number of possible structural isomers also increases with the consequence that the nascent species may adopt a different spatial arrangement, to the lowest energy one. As part of a program of investigations of the hydrogen atom transfer reaction or tautomerization of imidic acid–amide species H‐O=C‐N‐ O=C‐N‐H we have studied the kinetics for a number of nucleobases, namely cytosine, thymine and uracil where a cyclic form of tautomerism (lactim–lactam) is encountered. Together with a fourth, 5‐aza‐uracil (1,3,5‐triazine‐2,4(1H,3H)‐dione), we report on the rates of reaction at low temperatures 50–200 K for both the direct unimolecular process and the similar transformation mediated by an additional water molecule. We show that these tautomerization reactions can be categorized into three classes, and highlight the importance of quantum mechanical tunneling on the rate constants at these low temperatures. We further present some thermochemistry data, such as formation enthalpies, entropies, isobaric heat capacities and enthalpy functions.

Combination of quinoxaline with pentamethinium system: Mitochondrial staining and targeting

Pentamethinium indolium salts are promising fluorescence probes and anticancer agents with high mitochondrial selectivity. We synthesized two indolium pentamethinium salts: a cyclic form with quinoxaline directly incorporated in the pentamethinium chain (cPMS) and an open form with quinoxaline substitution in the γ-position (oPMS). To better understand their properties, we studied their interaction with mitochondrial phospholipids (cardiolipin and phosphatidylcholine) by spectroscopic methods (UV–Vis, fluorescence, and NMR spectroscopy). Both compounds displayed significant affinity for cardiolipin and phosphatidylcholine, which was associated with a strong change in their UV–Vis spectra. Nevertheless, we surprisingly observed that fluorescence properties of cPMS changed in complex with both cardiolipin and phosphatidylcholine, whereas those of oPMS only changed in complex with cardiolipin. Both salts, especially cPMS, display high usability in mitochondrial imaging and are cytotoxic for cancer cells. The above clearly indicates that conjugates of pentamethinium and quinoxaline group, especially cPMS, represent promising structural motifs for designing mitochondrial-specific agents.

A novel cyclic peptide library immobilized on gel-type beads focusing on rapid construction and characterization for comprehensive drug discovery.

Medium sized molecules such as peptides and macrocycles have recently drawn much attention as potent sources of medicinal lead compounds, whereas the possibility of obtaining a practical drug from them remains limited. The present paper describes a concept of discovering novel medicinal targets or binding modes as well as lead compounds by the one-peptide-on-one-bead (OPOB) technology for comprehensive screening. The difficulty and problems in conventional drug discovery methods that generally deal with one predetermined target are considered. The building blocks used for the present libraries were selected based on previous results in development of peptidic drugs. Each constituent has the common structure of cyclic form prepared by disulfide of cysteinyl residues or thioether linkages, additionally a methionine residue was inserted for the site-specific rapid cleavage by cyanogen bromide to liberate the immobilized peptides allowing reliable characterization by MALDI-TOF-MS/MS without LC-purification. Thus, a high throughput construction method for cyclic peptide libraries as well as characterization of single bead are proposed for drug discovery.

Penerapan Model Pembelajaran Cooperative Learning Tipe Snowball Throwing untuk Meningkatkan Sikap Percaya Diri Dan Tanggung Jawab

This study aims to describe the application of the Snowball Throwing type Cooperative Learning model and increase the self-confidence and responsible attitudes of third-grade students of SD Negeri 02 Kabawetan. This research is classroom action research. The subjects of this study were 16 students consisting of 7 male students and 9 female students. The research procedure is in cyclic form. Each cycle consists of four stages including Planning, implementing actions, observing and reflecting. This research data collection technique using observation techniques. The research instrument was a self-confidence and responsibility observation sheet. The data analysis technique used is the observation sheet using a formula that is processed descriptively, namely quantitative analysis and the range of values for each criterion. The results of this study indicate that the application of the Snowball Throwing learning model has increased from cycle one to cycle two. This can be seen from the increase in students' self-confidence and responsibility. The results of the observation of the assessment of students' self-confidence in the first cycle obtained that 55.30% was included in the sufficient category. Then the increase in the results of the observation of the second cycle was obtained that 75.93% was included in the Good category, while the results of the observation on the assessment of the responsibility of students' attitudes were obtained, namely, 57.98% included in the sufficient category Then the increase in the observation results of the second cycle was obtained that 77.70% was included in the good category. Thus, the application of the Snowball Throwing model can increase the self-confidence and responsibility of third-grade students of Elementary School 02 Kabawetan. 

A density functional theory study on how γ-Al2O3 – Boehmite transformation affects carbon evolution during aqueous-phase reaction

Gamma-alumina (γ-Al2O3), one of the most common materials, is commercially used in many catalytic applications, including the active catalyst and support. However, the problem of fast deactivation makes the utilization of the γ-Al2O3 challenging. This work elucidates the mechanism of coke formation consisting of coke deposition and evolution on γ-Al2O3(110) surfaces in differential conditions, including; clean and hydroxylation γ-Al2O3(110) in terms of partial and fully hydroxylation of OH/γ-Al2O3(110) and AlOOH(010), respectively. We demonstrated that the γ-Al2O3(110) surface is proper for atomic coke deposition and dimerization in the initial state, where the presence of OH species promotes the coke evolution to higher coke, Cn (where n ≥ 3). Also, the higher coke formation thermodynamically preferred the cyclic form to the aliphatic one. The electron transfer from substrates to adsorbed coke illustrates the role of the electron donor of catalyst surfaces corresponding to the electron acceptor of adsorbed cokes.

A DAPSI(W)R(M) framework approach to characterization of environmental issues in touristic coastal systems. An example from Southern Spain

Coasts are complex natural and human systems subject to change via natural processes and human activity. Assimilation of this diverse set of drivers and responses and the relationships between them is a challenge in coastal management. We investigate the utility of the DAPSI(W)R(M) framework to identify indicators of environmental issues and the relations between human activities and the environment through a practical application on a coast with high levels of tourism-related activities. Components and indicators were assessed by a review of literature and existing data in the Málaga Province of southern Spain, focusing on coastal erosion and its relationship to the natural environment and social systems. The results indicate the utility of the DAPSI(W)R(M) framework to characterize key environmental issues that affect coastal areas, and provide an holistic vision of human activities and environmental processes. The application of this approach can improve coastal management through the development of a simple model that characterizes environmental issues from the causes to the consequences by means of indicators and the relationships between them. The cyclic form of the model permits an easy identification of where problems occur and who is involved with their resolution, helping with stakeholder mapping and decision-making regarding appropriate responses that can be taken to other administrative levels or other heavily developed tourist coastal areas.

Structure-function analysis of an ancient TsaD-TsaC-SUA5-TcdA modular enzyme reveals a prototype of tRNA t6A and ct6A synthetases.

N 6-threonylcarbamoyladenosine (t6A) is a post-transcriptional modification found uniquely at position 37 of tRNAs that decipher ANN-codons in the three domains of life. tRNA t6A plays a pivotal role in promoting translational fidelity and maintaining protein homeostasis. The biosynthesis of tRNA t6A requires members from two evolutionarily conserved protein families TsaC/Sua5 and TsaD/Kae1/Qri7, and a varying number of auxiliary proteins. Furthermore, tRNA t6A is modified into a cyclic hydantoin form of t6A (ct6A) by TcdA in bacteria. In this work, we have identified a TsaD-TsaC-SUA5-TcdA modular protein (TsaN) from Pandoraviruses and determined a 3.2 Å resolution cryo-EM structure of P. salinus TsaN. The four domains of TsaN share strong structural similarities with TsaD/Kae1/Qri7 proteins, TsaC/Sua5 proteins, and Escherichia coli TcdA. TsaN catalyzes the formation of threonylcarbamoyladenylate (TC-AMP) using L-threonine, HCO3- and ATP, but does not participate further in tRNA t6A biosynthesis. We report for the first time that TsaN catalyzes a tRNA-independent threonylcarbamoyl modification of adenosine phosphates, leading to t6ADP and t6ATP. Moreover, TsaN is also active in catalyzing tRNA-independent conversion of t6A nucleoside to ct6A. Our results imply that TsaN from Pandoraviruses might be a prototype of the tRNA t6A- and ct6A-modifying enzymes in some cellular organisms.

Natural and synthetic peptides in antimicrobial therapy

Antimicrobial function of innate immunity is mediated by the low-molecular weight peptides which are active against bacteria, fungi and some viruses. The review presents data on studies of both natural and synthetic peptides regarding the features of their structure and therapeutic effect. As a rule, the molecules of such peptides are positively charged, due to amino acid radicals capable of protonation. Spatially, antimicrobial peptide molecules are arranged as -helices or -layers in separate or compound assemblies. At the same time, short molecular chains, including up to 18 amino acid residues, exist as a linear or cyclic forms, remaining at the level of primary spatial structure. Natural antimicrobial peptides are predominantly produced by neutrophilic granulocytes and macrophages, as well as epithelial cells of the barrier organs. Three families of natural antimicrobial peptides have been most studied: defensins, cathelicidins, and histatins. Defensins are active against Gram-positive and Gram-negative bacteria, viruses and fungi, having anti-inflammatory and immunomodulatory activity. Cathelicidins are chemoattractants and exert antibacterial, immunomodulatory, wound healing, antitumor effects, potentially contributing to the development of autoimmune diseases. Histatins have a pronounced fungicidal effect and prevent the formation of bacterial biofilms. A detailed study on the structure and principles of action of natural antimicrobial peptides made it possible to apply this information for the in vitro synthesis of peptides thus making it possible to create multipurpose drugs based on them. E.g., synthetic peptides WR12 and D-IK8 ensure the delivery of antibiotics to infected or tumor cells, due to permeabilization of cellular membranes. At the same time, a synthetic peptide, acipensin 1, is capable of penetrating into human tumor cells without damaging them. The immunomodulatory peptide glutoxim is effectively used in anti-tuberculosis therapy. ZP2 peptide, the functional site of granulocyte-macrophage colony-stimulating factor is effective against Gram-negative bacteria (K. pneumoniae, P. aeruginosa and A. baumannii) as well as EpsteinBarr virus. Thymic immunoregulatory peptides bestim, hepon, thymogen and imunofan are inducers of endogenous - and -interferon production, inhibit the development of malignant neoplasms, and possess anti-inflammatory activity. Gepon is used in the treatment of viral hepatitis, respiratory and opportunistic infections, croup syndrome and sexually transmitted infections (including genital herpes). Thus, the synthetic antimicrobial peptides are widely used in complex treatment regimens along with conventional antibiotics, antiviral, and antitumor drugs, thus making it possible to achieve higher therapeutic effect.

Cyclic forms on DG-Lie algebroids and semiregularity

Cyclic forms on DG-Lie algebroids and semiregularity

Low Frequency Cyclic Mechanical Loading of Till Deposits from Northern Germany under Oedometric Conditions

Glacial deposits are of significant importance to geotechnical engineers and geologists in northern Europe, North America, and Northern Asia, as vast areas of these land surfaces were historically covered with ice leading to the formation of a wide variety of till deposits. The use of these areas for various engineering purposes warrants their subjection to mechanical loads (of static and cyclic forms) from manmade structures, as well as natural hazards such as earthquakes. This paper focuses on the experimental investigation of the cyclic mechanical loading behavior of two glacial tills from northern Germany under one-dimensional loading or oedometric conditions, and in different soil wetting conditions. The experimental results show a significant dependence of the cyclic mechanical response of the glacial tills on wetting condition and number of loading cycles. The recorded values of accumulated plastic strains of the glacial tills generally increase with an increase in wetting or moisture content, with the highest measured value for the two tills being around 3.9% after 19 cycles of loading. The findings of the experimental cyclic mechanical tests of the glacial tills are discussed in view of the intrinsic soil behavior and fabric.

Novel Vaccine against Pathological Pyroglutamate-Modified Amyloid Beta for Prevention of Alzheimer's Disease.

Post-translationally modified N-terminally truncated amyloid beta peptide with a cyclized form of glutamate at position 3 (pE3Aβ) is a highly pathogenic molecule with increased neurotoxicity and propensity for aggregation. In the brains of Alzheimer's Disease (AD) cases, pE3Aβ represents a major constituent of the amyloid plaque. The data show that pE3Aβ formation is increased at early pre-symptomatic disease stages, while tau phosphorylation and aggregation mostly occur at later stages of the disease. This suggests that pE3Aβ accumulation may be an early event in the disease pathogenesis and can be prophylactically targeted to prevent the onset of AD. The vaccine (AV-1986R/A) was generated by chemically conjugating the pE3Aβ3-11 fragment to our universal immunogenic vaccine platform MultiTEP, then formulated in AdvaxCpG adjuvant. AV-1986R/A showed high immunogenicity and selectivity, with endpoint titers in the range of 105-106 against pE3Aβ and 103-104 against the full-sized peptide in the 5XFAD AD mouse model. The vaccination showed efficient clearance of the pathology, including non-pyroglutamate-modified plaques, from the mice brains. AV-1986R/A is a novel promising candidate for the immunoprevention of AD. It is the first late preclinical candidate which selectively targets a pathology-specific form of amyloid with minimal immunoreactivity against the full-size peptide. Successful translation into clinic may offer a new avenue for the prevention of AD via vaccination of cognitively unimpaired individuals at risk of disease.