Soraya S. Bosch

Toscana Life Sciences

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Carsten Wrenger

Universidade de São Paulo

Matthew R. Groves

University of Groningen

Fernando de Assis Batista

Institut Pasteur

Sergey Lunev

University of Groningen

Marleen Linzke

Universidade de São Paulo

Alexander Dömlingꝉ

Institute of Technology and Business

Giampiero Batani

Toscana Life Sciences

Yuwei Shen

Hartford Hospital

Marco Falcone

University of Pisa

Thales Kronenberger

University of Eastern Finland

Cooperative Institutions

Toscana Life Sciences

University of Siena

University of Groningen

Universidade de São Paulo

University of Pisa

Azienda Ospedaliera Universitaria Pisana

University of Turin

Bernhard Nocht Institute for Tropical Medicine

California Institute of Technology

National Research Council

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Oligomeric protein interference validates druggability of aspartate interconversion in Plasmodium falciparum

MicrobiologyOpen (2019)

Fernando de Assis Batista Soraya S. Bosch Sabine Butzloff Sergey Lunev Kamila Anna Meissner

The appearance of multi-drug resistant strains of malaria poses a major challenge to human health and validated drug targets are urgently required. To define a protein's function in vivo and thereby validate it as a drug target, highly specific tools are required that modify protein function with minimal cross-reactivity. While modern genetic approaches often offer the desired level of target specificity, applying these techniques is frequently challenging-particularly in the most dangerous malaria parasite, Plasmodium falciparum. Our hypothesis is that such challenges can be addressed by incorporating mutant proteins within oligomeric protein complexes of the target organism in vivo. In this manuscript, we provide data to support our hypothesis by demonstrating that recombinant expression of mutant proteins within P. falciparum leverages the native protein oligomeric state to influence protein function in vivo, thereby providing a rapid validation of potential drug targets. Our data show that interference with aspartate metabolism in vivo leads to a significant hindrance in parasite survival and strongly suggest that enzymes integral to aspartate metabolism are promising targets for the discovery of novel antimalarials.

Druggability

10.1002/mbo3.779

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Citations (7)

Analysis of the ATCase catalysis within the amino acid metabolism of the human malaria parasite Plasmodium falciparum

Soraya S. Bosch

Malaria, caused by Plasmodium spp., remains with more than 400.000 deaths per year one of the devastating diseases of our time. Plasmodium falciparum, which causes tropical malaria, is the most dangerous one leading to severe malaria. The aim of this thesis was to evaluate the necessity of the aspartate carbamoyltransferase (ATCase) within the aspartate metabolism of the human malaria parasite Plasmodium falciparum. The respective open reading frame has been identified and was cloned; with the encoded enzyme recombinantly expressed we could get conformational and kinetic insights by crystallization experiments, we could resolve the crystal structure of the enzyme, in “T’ (tense) and “R’ (relaxed) states. Moreover, in this work, we show the importance of the PfATCase for the proliferation of the malaria parasite by mutagenic studies and protein interference experiments. As predicted by bioinformatic tools the protein bears an apicoplast-targeting sequence and therefore its localization was determined here. Furthermore, this work is focusing on the ATCase as a drug target, dose-response experiments and protein interference studies with in vivo parasites, proves our hypothesis and the drugability of the enzyme.

Apicoplast

Plasmodium (life cycle)

Aspartate carbamoyltransferase

Source

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Citations (0)

Oxidative Stress Control by Apicomplexan Parasites

BioMed Research International (2015)

Soraya S. Bosch Thales Kronenberger Kamila Anna Meissner Flávia M. Zimbres Dirk Stegehake

Apicomplexan parasites cause infectious diseases that are either a severe public health problem or an economic burden. In this paper we will shed light on how oxidative stress can influence the host-pathogen relationship by focusing on three major diseases: babesiosis, coccidiosis, and toxoplasmosis.

Toxoplasmosis

10.1155/2015/351289

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Citations (49)

Anti-capsule human monoclonal antibodies protect against hypervirulent and pandrug-resistant Klebsiella pneumoniae

Research Square (Research Square) (2024)

Anna Kabanova Emanuele Roscioli V. Fonseca Soraya S. Bosch Ida Paciello

Abstract The silent pandemic caused by antimicrobial resistance (AMR) requires innovative therapeutic approaches. Human monoclonal antibodies (mAbs), which are among the most transformative, safe and effective drugs in oncology and autoimmunity, are rarely used for infectious diseases and not yet used for AMR. Here we applied an antigen-agnostic strategy to isolate extremely potent human mAbs against Klebsiella pneumoniae (Kp) sequence type 147 (ST147), a hypervirulent and pandrug-resistant clonotype which is spreading globally. Isolated mAbs target the bacterial capsule and the O-antigen. Surprisingly, although both capsule- and O-antigen-specific mAbs displayed bactericidal activity in the picomolar range in vitro, only the capsule-specific mAbs were protective against fulminant ST147 bloodstream infection. Protection correlated with in vitro bacterial uptake by macrophages and enchained bacterial growth. Our study describes the only therapeutic able to protect against pandrug-resistant Kp and provides a strategy to isolate mAbs and identify correlates of protection against AMR bacteria.

Capsule

10.21203/rs.3.rs-4631260/v1

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Citations (1)

Identification of a non-competitive inhibitor of Plasmodium falciparum aspartate transcarbamoylase

Biochemical and Biophysical Research Communications (2018)

Sergey Lunev Soraya S. Bosch Fernando de Assis Batista Chao Wang Jingyao Li

Aspartate transcarbamoylase catalyzes the second step of de-novo pyrimidine biosynthesis. As malarial parasites lack pyrimidine salvage machinery and rely on de-novo production for growth and proliferation, this pathway is a target for drug discovery. Previously, an apo crystal structure of aspartate transcarbamoylase from Plasmodium falciparum (PfATC) in its T-state has been reported. Here we present crystal structures of PfATC in the liganded R-state as well as in complex with the novel inhibitor, 2,3-napthalenediol, identified by high-throughput screening. Our data shows that 2,3-napthalediol binds in close proximity to the active site, implying an allosteric mechanism of inhibition. Furthermore, we report biophysical characterization of 2,3-napthalenediol. These data provide a promising starting point for structure based drug design targeting PfATC and malarial de-novo pyrimidine biosynthesis.

Aspartate carbamoyltransferase

Pyrimidine metabolism

10.1016/j.bbrc.2018.02.112

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Citations (19)

Crystal structure of truncated aspartate transcarbamoylase fromPlasmodium falciparum

Acta Crystallographica Section F Structural Biology Communications (2016)

Sergey Lunev Soraya S. Bosch Fernando de Assis Batista Carsten Wrenger Matthew R. Groves

The de novo pyrimidine-biosynthesis pathway of Plasmodium falciparum is a promising target for antimalarial drug discovery. The parasite requires a supply of purines and pyrimidines for growth and proliferation and is unable to take up pyrimidines from the host. Direct (or indirect) inhibition of de novo pyrimidine biosynthesis via dihydroorotate dehydrogenase ( Pf DHODH), the fourth enzyme of the pathway, has already been shown to be lethal to the parasite. In the second step of the plasmodial pyrimidine-synthesis pathway, aspartate and carbamoyl phosphate are condensed to N -carbamoyl-L-aspartate and inorganic phosphate by aspartate transcarbamoylase ( Pf ATC). In this paper, the 2.5 Å resolution crystal structure of Pf ATC is reported. The space group of the Pf ATC crystals was determined to be monoclinic P 2 1 , with unit-cell parameters a = 87.0, b = 103.8, c = 87.1 Å, α = 90.0, β = 117.7, γ = 90.0°. The presented Pf ATC model shares a high degree of homology with the catalytic domain of Escherichia coli ATC. There is as yet no evidence of the existence of a regulatory domain in Pf ATC. Similarly to E. coli ATC, Pf ATC was modelled as a homotrimer in which each of the three active sites is formed at the oligomeric interface. Each active site comprises residues from two adjacent subunits in the trimer with a high degree of evolutional conservation. Here, the activity loss owing to mutagenesis of the key active-site residues is also described.

Aspartate carbamoyltransferase

Pyrimidine metabolism

Dihydroorotate Dehydrogenase

Thermotoga maritima

Transferase

Carbamoyl phosphate synthetase

10.1107/s2053230x16008475

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Citations (15)

Análise da catálise da Aspartato Carbamoyltransferase dentro do metabolismo de aminoácidos do parasita efetor da malária humana >i<Plasmodium falciparum>/i<.

Soraya S. Bosch

Esta tesis está dedicada a

10.11606/t.42.2019.tde-14032023-171803

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Identification and Validation of Novel Drug Targets for the Treatment of Plasmodium falciparum Malaria: New Insights

InTech eBooks (2016)

Sergey Lunev Fernando de Assis Batista Soraya S. Bosch Carsten Wrenger Matthew R. Groves

In order to counter the malarial parasite's striking ability to rapidly develop drug resistance, a constant supply of novel antimalarial drugs and potential drug targets must be available. The so-called Harlow-Knapp effect, or "searching under the lamp post," in which scientists tend to further explore only the areas that are already well illuminated, significantly limits the availability of novel drugs and drug targets. This chapter summarizes the pool of electron transport chain (ETC) and carbon metabolism antimalarial targets that have been "under the lamp post" in recent years, as well as suggest a promising new avenue for the validation of novel drug targets. The interplay between the pathways crucial for the parasite, such as pyrimidine biosynthesis, aspartate metabolism, and mitochondrial tricarboxylic acid (TCA) cycle, is described in order to create a "road map" of novel antimalarial avenues.

Malarial parasites

Plasmodium (life cycle)

10.5772/65659

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Citations (18)

Molecular Target Validation of Aspartate Transcarbamoylase from Plasmodium falciparum by Torin 2

ACS Infectious Diseases (2020)

Soraya S. Bosch Sergey Lunev Fernando de Assis Batista Marleen Linzke Thales Kronenberger

Malaria is a tropical disease that kills about half a million people around the world annually. Enzymatic reactions within pyrimidine biosynthesis have been proven to be essential for Plasmodium proliferation. Here we report on the essentiality of the second enzymatic step of the pyrimidine biosynthesis pathway, catalyzed by aspartate transcarbamoylase (ATC). Crystallization experiments using a double mutant ofPlasmodium falciparum ATC (PfATC) revealed the importance of the mutated residues for enzyme catalysis. Subsequently, this mutant was employed in protein interference assays (PIAs), which resulted in inhibition of parasite proliferation when parasites transfected with the double mutant were cultivated in medium lacking an excess of nutrients, including aspartate. Addition of 5 or 10 mg/L of aspartate to the minimal medium restored the parasites' normal growth rate. In vitro and whole-cell assays in the presence of the compound Torin 2 showed inhibition of specific activity and parasite growth, respectively. In silico analyses revealed the potential binding mode of Torin 2 to PfATC. Furthermore, a transgenic ATC-overexpressing cell line exhibited a 10-fold increased tolerance to Torin 2 compared with control cultures. Taken together, our results confirm the antimalarial activity of Torin 2, suggesting PfATC as a target of this drug and a promising target for the development of novel antimalarials.

Pyrimidine metabolism

Aspartate carbamoyltransferase

10.1021/acsinfecdis.9b00411

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Citations (10)

Anti-capsule human monoclonal antibodies protect against hypervirulent and pandrug-resistantKlebsiella pneumoniae

bioRxiv (Cold Spring Harbor Laboratory) (2024)

Emanuele Roscioli V. Fonseca Soraya S. Bosch Ida Paciello Giuseppe Maccari

SUMMARY The silent pandemic caused by antimicrobial resistance (AMR) requires innovative therapeutic approaches. Human monoclonal antibodies (mAbs), which are among the most transformative, safe and effective drugs in oncology and autoimmunity, are rarely used for infectious diseases and not yet used for AMR. Here we applied an antigen-agnostic strategy to isolate extremely potent human mAbs against Klebsiella pneumoniae (Kp) sequence type 147 (ST147), a hypervirulent and pandrug-resistant clonotype which is spreading globally. Isolated mAbs target the bacterial capsule and the O-antigen. Surprisingly, although both capsule- and O-antigen-specific mAbs displayed bactericidal activity in the picomolar range in vitro , only the capsule-specific mAbs were protective against fulminant ST147 bloodstream infection. Protection correlated with in vitro bacterial uptake by macrophages and enchained bacterial growth. Our study describes the only drug able to protect against pandrug-resistant Kp and provides a strategy to isolate mAbs and identify correlates of protection against AMR bacteria.

Bacterial capsule

10.1101/2024.02.14.580141

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Citations (3)