Peptidotriazolamers Inhibit A beta(1-42) Oligomerization and Cross a Blood-Brain-Barrier Model

In peptidotriazolamers every second peptide bond is replaced by a 1H-1,2,3-triazole. Such foldamers are expected to bridge the gap in molecular weight between small-molecule drugs and protein-based drugs. Amyloid beta (A beta) aggregates play an important role in Alzheimer's disease. We studied the impact of amide bond replacements by 1,4-disubstituted 1H-1,2,3-triazoles on the inhibitory activity of the aggregation "hot spots" (KLVFF20)-L-16 and G(39)VVIA(42) in A beta(1-42). We found that peptidotriazolamers act as modulators of the A beta(1-42) oligomerization. Some peptidotriazolamers are able to interfere with the formation of toxic early A beta oligomers, depending on the position of the triazoles, which is also supported by computational studies. Preliminary in vitro results demonstrate that a highly active peptidotriazolamer is also able to cross the blood-brain-barrier.Peer reviewe

Designed glycopeptidomimetics disrupt protein−protein interactions mediating amyloid β‑peptide aggregation and restore neuroblastoma cell viability

How anti-Alzheimer’s drug candidates that reduce amyloid 1−42 peptide fibrillization interact with the most neurotoxic species is far from being understood. We report herein the capacity of sugar-based peptidomimetics to inhibit both Aβ1−42 early oligomerization and fibrillization. A wide range of bio- and physicochemical techniques, such as a new capillary electrophoresis method, nuclear magnetic resonance, and surface plasmon resonance, were used to identify how these new molecules can delay the aggregation of Aβ1−42. We demonstrate that these molecules interact with soluble oligomers in order to maintain the presence of nontoxic monomers and to prevent fibrillization. These compounds totally suppress the toxicity of Aβ1−42 toward SH-SY5Y neuroblastoma cells, even at substoichiometric concentrations. Furthermore, demonstration that the best molecule combines hydrophobic moieties, hydrogen bond donors and acceptors, ammonium groups, and a hydrophilic β-sheet breaker element provides valuable insight for the future structure-based design of inhibitors of Aβ1−42 aggregation

Conception, synthèse et évaluation biologique de nouveaux analogues de la combrétastatine A4, agents antivasculaires potentiels

Combretastatin A4, a drug isolated from Combretum caffrum, is a microtubule depolymerizing agent, and a vascular targeting agent; it causes a prolonged and extensive shut-down of blood flow in established tumour blood vessels, leading to massive hemorrhagic necrosis by lack of oxygen and nutriments. Our aim was to identify new combretastatin A4 analogues with high potential antitubulin activity. Three types of pharmacomodulation based on the nature of the bridge (cis-ethylenic) connecting both aromatic rings were undertaken, in view of maintaining the required conformation essential for bioactivity: - heterocyclic analogues in which the double bond is replaced by different heterocycles ( [1,3]-dipolar cycloaddition reactions), - vinylogous derivatives (diarylbutadiene by Suzuki-Miyaura reactions) and their cyclopropyl locked analogues. One of these compounds is three times more potent than combretastatin A4.La combrétastatine A4, dérivé isolé de Combretum caffrum, inhibiteur de la polymérisation de la tubuline, présente un effet sur la vascularisation des tumeurs expérimentales : diminution importante et quasi-immédiate du flux sanguin au niveau de la tumeur qui, en hypoxie, se nécrose. Notre objectif était d'identifier de nouveaux analogues de la CA4 qui seraient de puissants inhibiteurs de polymérisation de la tubuline. Trois types de pharmacomodulation ont été entrepris portant sur la nature du pont (éthylénique cis) reliant les deux noyaux aromatiques, afin de figer la molécule dans la conformation requise pour une activité optimale: - analogues hétérocycliques : la double liaison est remplacée par des hétérocycles de type isoxazole (réactions de cycloadditions [1,3]-dipolaires), - vinylogues de la CA4 (diarylbutadiènes par réaction de Suzuki-Miyaura) et leurs analogue rigidifiés par un motif cyclopropane. Un composé de ces séries est trois fois plus actif que la combrétastatine A4.PARIS-BIUP (751062107) / SudocSudocFranceF

Early Effects of Combretastatin A4 Phosphate Assessed by Anatomic and Carbogen-Based Functional Magnetic Resonance Imaging on Rat Bladder Tumors Implanted in Nude Mice

Combretastatin A4 phosphate (CA4P) causes rapid disruption of the tumor vasculature and is currently being evaluated for antivascular therapy. We describe the initial results obtained with a noninvasive multi-parametric magnetic resonance imaging (MRI) approach to assess the early effects of CA4P on rat bladder tumors implanted on nude mice. MRI (4.7 T) comprised a fast spin-echo sequence for growth curve assessment; a multislice multiecho sequence for T(2) measurement before, 15 minutes after, and 24 hours after CA4P (100 mg/kg); and a fast T(2w)* gradient-echo sequence to assess MR signal modification under carbogen breathing before, 35 minutes after, and 24 hours after CA4P. The tumor fraction with increased T(2w)* signal intensity under carbogen (T(+)) was used to quantify CA4P effect on functional vasculature. CA4P slowed tumor growth over 24 hours and accelerated necrosis development. T(+) decrease was observed already at 35 minutes post-CA4P. Early T(2) increase was observed in regions becoming necrotic at 24 hours post-CA4P, as confirmed by high T(2) and histology. These regions exhibited, under carbogen, a switch from T(2w)* signal increase before CA4P to a decrease post-CA4P. The combination of carbogen-based functional MRI and T(2) measurement may be useful for the early follow-up of antivascular therapy without the administration of contrast agents

Evidence for different in vitro oligomerization behaviors of synthetic hIAPP obtained from different sources

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Real-Time BODIPY-Binding Assay To Screen Inhibitors of the Early Oligomerization Process of A beta 1-42 Peptide

Tonali NM, Dodero VI, Kaffy J, Hericks L, Ongeri S, Sewald N. Real-Time BODIPY-Binding Assay To Screen Inhibitors of the Early Oligomerization Process of A beta 1-42 Peptide. ChemBioChem. 2020;21(8):1129-1135.Misfolding and aggregation of amyloid beta 1-42 peptide (A beta 1-42) play a central role in the pathogenesis of Alzheimer's disease (AD). Targeting the highly cytotoxic oligomeric species formed during the early stages of the aggregation process represents a promising therapeutic strategy to reduce the toxicity associated with A beta 1-42. Currently, the thioflavin T (ThT) assay is the only established spectrofluorometric method to screen aggregation inhibitors. The success of the ThT assay is that it can detect A beta 1-42 aggregates with high beta-sheet content, such as protofibrils or fibrils, which appear in the late aggregation steps. Unfortunately, by using the ThT assay, the detection of inhibitors of early soluble oligomers that present a low beta-sheet character is challenging. Herein, a new, facile, and robust boron-dipyrromethene (BODIPY) real-time assay suitable for 96-well plate format, which allows screening of compounds as selective inhibitors of the formation of A beta 1-42 oligomers, is reported. These inhibitors decrease the cellular toxicity of A beta 1-42, although they fail in the ThT assay. The findings have been confirmed and validated by structural analysis and cell viability assays under comparable experimental conditions. It is demonstrated that the BODIPY assay is a convenient method to screen and discover new candidate compounds that slow down or stop the pathological early oligomerization process and are active in the cellular assay. Therefore, it is a suitable complementary screening method of the current ThT assay

Evidence for different in vitro oligomerization behavior for synthetic hIAPP obtained from different sources

International audienc

Evidence for different in vitro oligomerization behavior for synthetic hIAPP obtained from different sources

International audienc

Towards a general synthesis of di-aza-amino acids containing peptides

International audienc

Evidence for different in vitro oligomerization behavior for synthetic hIAPP obtained from different sources

International audienc