Computational Assessment of Bacterial Protein Structures Indicates a Selection Against Aggregation

Čarija, Anita; Pinheiro, Francisca; Iglesias, Valentín; Ventura, Salvador

doi:10.3390/cells8080856

Cited by 10 publications

(6 citation statements)

References 67 publications

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“…Protein abundance and aggregation propensity were calculated and plotted as elsewhere described [ 91 ]. Briefly, abundance (C) was calculated as the log 10 of the protein concentration values obtained from PaxDb [ 92 ], which were normalized by rescaling them between 0 and 1: …”

Section: Methodsmentioning

confidence: 99%

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

et al. 2022

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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.

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Section: Methodsmentioning

confidence: 99%

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

et al. 2022

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“…The abundance and aggregation propensity of each protein in the proteome were calculated and plotted as described elsewhere (76). Briefly, abundance (C) was calculated as the log 10 of the protein concentration values obtained from PaxDb (77), which were normalized by rescaling them between 0 and 1 as follows:…”

Section: Methodsmentioning

confidence: 99%

Detection of Protein Aggregation in Live Plasmodium Parasites

Biosca

Bouzón‐Arnáiz

Spanos

et al. 2020

Antimicrob Agents Chemother

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The rapid evolution of resistance in the malaria parasite to every single drug developed against it calls for the urgent identification of new molecular targets. Using a stain specific for the detection of intracellular amyloid deposits in live cells, we have detected the presence of abundant protein aggregates in Plasmodium falciparum blood stages and female gametes cultured in vitro, in the blood stages of mice infected by Plasmodium yoelii, and in the mosquito stages of the murine malaria species Plasmodium berghei. Aggregated proteins could not be detected in early rings, the parasite form that starts the intraerythrocytic cycle. A proteomics approach was used to pinpoint actual aggregating polypeptides in functional P. falciparum blood stages, which resulted in the identification of 369 proteins, with roles particularly enriched in nuclear import-related processes. Five aggregation-prone short peptides selected from this protein pool exhibited different aggregation propensity according to Thioflavin-T fluorescence measurements, and were observed to form amorphous aggregates and amyloid fibrils in transmission electron microscope images. The results presented suggest that generalized protein aggregation might have a functional role in malaria parasites. Future antimalarial strategies based on the upsetting of the pathogen’s proteostasis and therefore affecting multiple gene products could represent the entry to new therapeutic approaches.

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“…A3D outperforms classic sequence-and composition-based algorithms when dealing with globular proteins in their native conformations and can compute the effect of single or multiple user-defined mutations on protein stability and aggregation propensity, as well as automatically suggesting solubilizing amino acid changes. This algorithm has been employed to study the constraints imposed by aggregation on protein evolution (Carija et al, 2019), to diagnose the functional impact of genetic mutations (Seaby and Ennis, 2020), to predict the aggregation of the SARS-CoV-2 proteome (Flores-León et al, 2021), to assist the design of novel nanomaterials (Gil-Garcia and Ventura, 2021), or to engineer the solubility of therapeutic proteins (de Aguiar et al, 2021;Gil-Garcia et al, 2018) among many other applications.…”

Section: Introductionmentioning

confidence: 99%

A3D Database: Structure-based Protein Aggregation Predictions for the Human Proteome

Badaczewska-Dawid

García-Pardo

Kuriata

et al. 2021

Preprint

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MotivationProtein aggregation is associated with highly debilitating human disorders and constitutes a major bottleneck for producing therapeutic proteins. Our knowledge of the human protein structures repertoire has dramatically increased with the recent development of the AlphaFold (AF) deep-learning method. This structural information can be used to understand better protein aggregation properties and the rational design of protein solubility. This article uses the Aggrescan3D (A3D) tool to compute the structure-based aggregation predictions for the human proteome and make the predictions available in a database form.ResultsHere, we present the A3D Database, in which we analyze the AF-predicted human protein structures (for over 17 thousand non-membrane proteins) in terms of their aggregation properties using the A3D tool. Each entry of the A3D Database provides a detailed analysis of the structure-based aggregation propensity computed with A3D. The A3D Database implements simple but useful graphical tools for visualizing and interpreting protein structure datasets. We discuss case studies illustrating how the database could be used to analyze physiologically relevant proteins. Furthermore, the database enables testing the influence of user-selected mutations on protein solubility and stability, all integrated into a user-friendly interface.Availability and implementationA3D Database is freely available at: http://biocomp.chem.uw.edu.pl/A3D2/hproteome

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Computational Assessment of Bacterial Protein Structures Indicates a Selection Against Aggregation

Cited by 10 publications

References 67 publications

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

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

Detection of Protein Aggregation in Live Plasmodium Parasites

A3D Database: Structure-based Protein Aggregation Predictions for the Human Proteome

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