The protein aggregation inhibitor YAT2150 has potent antimalarial activity in Plasmodium falciparum in vitro cultures

© The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background: By 2016, signs of emergence of Plasmodium falciparum resistance to artemisinin and partner drugs were detected in the Greater Mekong Subregion. Recently, the independent evolution of artemisinin resistance has also been reported in Africa and South America. This alarming scenario calls for the urgent development of new antimalarials with novel modes of action. We investigated the interference with protein aggregation, which is potentially toxic for the cell and occurs abundantly in all Plasmodium stages, as a hitherto unexplored drug target in the pathogen. Results: Attempts to exacerbate the P. falciparum proteome's propensity to aggregation by delivering endogenous aggregative peptides to in vitro cultures of this parasite did not significantly affect their growth. In contrast, protein aggregation inhibitors clearly reduced the pathogen's viability. One such compound, the bis(styrylpyridinium) salt YAT2150, exhibited potent antiplasmodial activity with an in vitro IC50 of 90 nM for chloroquine- and artemisinin-resistant lines, arresting asexual blood parasites at the trophozoite stage, as well as interfering with the development of both sexual and hepatic forms of Plasmodium. At its IC50, this compound is a powerful inhibitor of the aggregation of the model amyloid β peptide fragment 1-40, and it reduces the amount of aggregated proteins in P. falciparum cultures, suggesting that the underlying antimalarial mechanism consists in a generalized impairment of proteostasis in the pathogen. YAT2150 has an easy, rapid, and inexpensive synthesis, and because it fluoresces when it accumulates in its main localization in the Plasmodium cytosol, it is a theranostic agent. Conclusions: Inhibiting protein aggregation in Plasmodium significantly reduces the parasite's viability in vitro. Since YAT2150 belongs to a novel structural class of antiplasmodials with a mode of action that potentially targets multiple gene products, rapid evolution of resistance to this drug is unlikely to occur, making it a promising compound for the post-artemisinin era.This work was supported by grants (i) PCIN-2017-100, RTI2018-094579-B-I00 and PID2021-128325OB-I00 (XF-B), and SAF2017-82771-R and PID2020-118127RB-I00 (DM-T), funded by Ministerio de Ciencia e Innovación/Agencia Estatal de Investigación (MCIN/AEI/10.13039/501100011033 for grants PID2021- and PID2020-), which for grants RTI2018-, PID2021-, and SAF2017- included FEDER funds; (ii) ERA-NET Cofund EURONANOMED (http://euronanomed.net/), grant number 2017-178 (XF-B); and (iii) Generalitat de Catalunya, Spain (http://agaur.gencat.cat/), grant numbers 2017-SGR-908 (XF-B) and 2017-SGR-106 (DM-T). Work at Pompeu Fabra University was supported by the “La Caixa” Banking Foundation (https://fundacionlacaixa.org/, grant HR17-00409), and by grant AGL2017-84097-C2-2-R and the “María de Maeztu” Program for Units of Excellence in R&D from the Spanish Ministry of Science, Innovation and Universities.info:eu-repo/semantics/publishedVersio

From virtual screening hits targeting a cryptic pocket in BACE-1 to a nontoxic brain permeable multitarget anti-Alzheimer lead with disease-modifying and cognition-enhancing effects

Starting from six potential hits identified in a virtual screening campaign directed to a cryptic pocket of BACE-1, at the edge of the catalytic cleft, we have synthesized and evaluated six hybrid compounds, designed to simultaneously reach BACE-1 secondary and catalytic sites and to exert additional activities of interest for Alzheimer's disease (AD). We have identified a lead compound with potent in vitro activity towards human BACE-1 and cholinesterases, moderate Ab42 and tau antiaggregating activity, and brain permeability, which is nontoxic in neuronal cells and zebrafish embryos at concentrations above those required for the in vitro activities. This compound completely restored short- and long-term memory in a mouse model of AD (SAMP8) relative to healthy control strain SAMR1, shifted APP processing towards the non-amyloidogenic pathway, reduced tau phosphorylation, and increased the levels of synaptic proteins PSD95 and synaptophysin, thereby emerging as a promising disease-modifying, cognitionenhancing anti-AD lead

Synthesis and Characterization of Polyaniline-Based Polymer Nanocomposites as Anti-Corrosion Coatings

Polymer nanocomposites of polyaniline (PANI)-based metal oxides (SiO2, CeO2, and TiO2A) were synthesized by in situ chemical oxidative polymerization by rapid mixing in a hydrochloric acid medium to evaluate and compare their performance as anti-corrosion coatings on commercial 1018 steel in a 3.5% NaCl medium. The anti-corrosion coatings were developed by dispersing synthesized nanocomposites on an alkydalic resin (AR) for their subsequent electrochemical characterization. X-ray diffraction (XRD) analyses show that PANI has a certain degree of crystallinity in its structure. The incorporation of metal oxide (MO) nanoparticles (NPs) into the polymer matrix was confirmed by scanning electron microscopy and energy-dispersive X-ray spectroscopy (SEM-EDS) analyses, while the interaction of nanoparticles with PANI was proven by Fourier transform infrared (FT-IR) and ultraviolet-visible (UV-vis). Thermogravimetric analysis (TGA) reveals that nanoparticles infer greater resistance to the thermal decomposition of PANI. Finally, the use of open circuit potential (OCP) study, Tafel curves, and electrochemical impedance spectroscopy (EIS) showed that coatings made with TiO2A NPs exhibit the best anti-corrosion properties as compared to those synthesized with SiO2 and CeO2 NPs

Efecto del calibre de la aguja sobre la eficacia de la hemodiálisis

Uno de los factores íntimamente relacionados con el aclaramiento de solutos durante la HD es el flujo de sangre; para que éste sea el adecuado es importante considerar el calibre de la aguja. Estudiamos el efecto de los cambios del calibre de la aguja sobre la eficacia de la DH considerando el tipo de acceso vascular. Se diseñó un estudio prospectivo en 66 pacientes en HD (48 con fístula nativa y 18 con protésica), en los que se modificó el calibre de la aguja. Se registró dolor, sangrado, tiempo de coagulación, presión venosa y KT/v. El uso de agujas 15G en la punción arterial mejora el aclaramiento de urea en las fístulas nativas pero no lo hace en las protésicas. El uso de agujas 14G provoca más episodios de dolor, sangrado periaguja y prolongación del tiempo de coagulación, por lo que recomendamos el uso de agujas 15G para conseguir una mayor eficacia en la HD a flujos de 350 ml/min

Unveiling the Multitarget Anti-Alzheimer Drug Discovery Landscape: A Bibliometric Analysis.

Multitarget anti-Alzheimer agents are the focus of very intensive research. Through a comprehensive bibliometric analysis of the publications in the period 1990-2020, we have identified trends and potential gaps that might guide future directions. We found that: (i) the number of publications boomed by 2011 and continued ascending in 2020; (ii) the linked-pharmacophore strategy was preferred over design approaches based on fusing or merging pharmacophores or privileged structures; (iii) a significant number of in vivo studies, mainly using the scopolamine-induced amnesia mouse model, have been performed, especially since 2017; (iv) China, Italy and Spain are the countries with the largest total number of publications on this topic, whereas Portugal, Spain and Italy are the countries in whose scientific communities this topic has generated greatest interest; (v) acetylcholinesterase, β-amyloid aggregation, oxidative stress, butyrylcholinesterase, and biometal chelation and the binary combinations thereof have been the most commonly pursued, while combinations based on other key targets, such as tau aggregation, glycogen synthase kinase-3β, NMDA receptors, and more than 70 other targets have been only marginally considered. These results might allow us to spot new design opportunities based on innovative target combinations to expand and diversify the repertoire of multitarget drug candidates and increase the likelihood of finding effective therapies for this devastating disease

Pauson-Khand reaction of internal dissymmetric trifluoromethyl alkynes. influence of the alkene on the regioselectivity

Abstract: The scope of the Pauson-Khand reaction (PKR) of internal trifluoromethyl alkynes, previously described with norbornadiene, is expanded to norbornene and ethylene. A thorough structural analysis of the resulting PK adducts has been carried out to unveil that α-trifluoromethylcyclopentenones are preferred in all cases, independently of the electronic properties of the alkyne. The regioselectivity observed with norbornadiene and ethylene is higher than in the case of norbornene

Effect of the aggregated protein dye YAT2150 on Leishmania parasite viability

The problems associated with the drugs currently used to treat leishmaniasis, including resistance, toxicity, and the high cost of some formulations, call for the urgent identification of new therapeutic agents with novel modes of action. The aggregated protein dye YAT2150 has been found to be a potent antileishmanial compound, with a half-maximal inhibitory concentration (IC50) of approximately 0.5 µM against promastigote and amastigote stages of Leishmania infantum. The encapsulation in liposomes of YAT2150 significantly improved its in vitro IC50 to 0.37 and 0.19 µM in promastigotes and amastigotes, respectively, and increased the half-maximal cytotoxic concentration in human umbilical vein endothelial cells to >50 µM. YAT2150 became strongly fluorescent when binding intracellular protein deposits in Leishmania cells. This fluorescence pattern aligns with the proposed mode of action of this drug in the malaria parasite Plasmodium falciparum, the inhibition of protein aggregation. In Leishmania major, YAT2150 rapidly reduced ATP levels, suggesting an alternative antileishmanial mechanism. To the best of our knowledge, this first-in-class compound is the only one described so far having significant activity against both Plasmodium and Leishmania, thus being a potential drug for the treatment of co-infections of both parasites.This work was supported by grants (i) Fundació La Marató de TV3, Ref. 201811 (X.F.-B.); (ii) PID2021-128325OB-I00 (X.F.-B.) and PID2020-118127RB-I00 (D.M.-T.), funded by Ministerio de Ciencia e Innovación/Agencia Estatal de Investigación (MCIN/AEI/10.13039/501100011033), which included ERDF funds; (iii) II Premis Innovació Campus Clínic 2022, Hospital Clínic de Barcelona (X.F.-B.); and (iv) Generalitat de Catalunya, Spain (http://agaur.gencat.cat/), grant numbers 2021-SGR-00635 (S.V.) and 2021-SGR-00357 (D.M.-T.). Work at Pompeu Fabra University was supported by “La Caixa” Banking Foundation (https://fundacionlacaixa.org/, grant HR17-00409) and by grant AGL2017-84097-C2-2-R and the “María de Maeztu” Program for Units of Excellence in R&D from the Spanish Ministry of Science, Innovation and Universities. Work at the Centro de Investigaciones Biológicas was supported by grants from MCIN Subdirección General de Redes y Centros de Investigación Cooperativa-FEDER RD16/0027/0010 and CSIC PIE 201620E038. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript