scholarly journals Identification and Characterization of Genes Involved in Leishmania Pathogenesis: The Potential for Drug Target Selection

2011 ◽  
Vol 2011 ◽  
pp. 1-10 ◽  
Author(s):  
Robert Duncan ◽  
Sreenivas Gannavaram ◽  
Ranadhir Dey ◽  
Alain Debrabant ◽  
Ines Lakhal-Naouar ◽  
...  
Keyword(s):  
Drug Targets ◽  
Leishmania Donovani ◽  
Target Selection ◽  
Life Cycle Stage ◽  
Cell Death Pathway ◽  
Ubiquitin System ◽  
Antiparasitic Drug ◽  
New Findings ◽  
Endoplasmic Reticulum Quality Control

Identifying and characterizing Leishmania donovani genes and the proteins they encode for their role in pathogenesis can reveal the value of this approach for finding new drug targets. Effective drug targets are likely to be proteins differentially expressed or required in the amastigote life cycle stage found in the patient. Several examples and their potential for chemotherapeutic disruption are presented. A pathway nearly ubiquitous in living cells targeted by anticancer drugs, the ubiquitin system, is examined. New findings in ubiquitin and ubiquitin-like modifiers in Leishmania show how disruption of those pathways could point to additional drug targets. The programmed cell death pathway, now recognized among protozoan parasites, is reviewed for some of its components and evidence that suggests they could be targeted for antiparasitic drug therapy. Finally, the endoplasmic reticulum quality control system is involved in secretion of many virulence factors. How disruptions in this pathway reduce virulence as evidence for potential drug targets is presented.

Molecular characterization of SARS-CoV-2

2020 ◽  
Vol 20 ◽  
Author(s):  
Miribane Dërmaku-Sopjani ◽  
Mentor Sopjani
Keyword(s):  
Public Health ◽  
Drug Targets ◽  
Virus Genome ◽  
Health Crisis ◽  
Public Health Crisis ◽  
Therapeutic Drugs ◽  
New Public Health ◽  
New Public ◽  
And Function

Abstract:: The coronavirus disease 2019 (COVID-19) is currently a new public health crisis threatening the world. This pandemic disease is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The virus has been reported to be originated in bats and by yet unknown intermediary animals were transmitted to humans in China 2019. The SARSCoV- 2 spreads faster than its two ancestors the SARS-CoV and Middle East respiratory syndrome coronavirus (MERSCoV) but has reduced fatality. At present, the SARS-CoV-2 has caused about a 1.16 million of deaths with more than 43.4 million confirmed cases worldwide, resulting in a serious threat to public health globally with yet uncertain impact. The disease is transmitted by inhalation or direct contact with an infected person. The incubation period ranges from 1 to 14 days. COVID-19 is accompanied by various symptoms, including cough, fatigue. In most people the disease is mild, but in some other people, such as in elderly and people with chronic diseases, it may progress from pneumonia to a multi-organ dysfunction. Many people are reported asymptomatic. The virus genome is sequenced, but new variants are reported. Numerous biochemical aspects of its structure and function are revealed. To date, no clinically approved vaccines and/or specific therapeutic drugs are available to prevent or treat the COVID-19. However, there are reported intensive researches on the SARSCoV- 2 to potentially identify vaccines and/or drug targets, which may help to overcome the disease. In this review, we discuss recent advances in understanding the molecular structure of SARS-CoV-2 and its biochemical characteristics.

scholarly journals DNA G-quadruplexes for native mass spectrometry in potassium: a database of validated structures in electrospray-compatible conditions

2021 ◽  
Author(s):  
Anirban Ghosh ◽  
Eric Largy ◽  
Valérie Gabelica
Keyword(s):  
Mass Spectrometry ◽  
Drug Targets ◽  
Native Mass Spectrometry ◽  
Drug Binding ◽  
Quadruplex Dna ◽  
Dna Structures ◽  
Nmr Structures ◽  
G Quadruplex ◽  
Screening Assays

Abstract G-quadruplex DNA structures have become attractive drug targets, and native mass spectrometry can provide detailed characterization of drug binding stoichiometry and affinity, potentially at high throughput. However, the G-quadruplex DNA polymorphism poses problems for interpreting ligand screening assays. In order to establish standardized MS-based screening assays, we studied 28 sequences with documented NMR structures in (usually ∼100 mM) potassium, and report here their circular dichroism (CD), melting temperature (Tm), NMR spectra and electrospray mass spectra in 1 mM KCl/100 mM trimethylammonium acetate. Based on these results, we make a short-list of sequences that adopt the same structure in the MS assay as reported by NMR, and provide recommendations on using them for MS-based assays. We also built an R-based open-source application to build and consult a database, wherein further sequences can be incorporated in the future. The application handles automatically most of the data processing, and allows generating custom figures and reports. The database is included in the g4dbr package (https://github.com/EricLarG4/g4dbr) and can be explored online (https://ericlarg4.github.io/G4_database.html).

scholarly journals New Findings in Prunus padus L. Fruits as a Source of Natural Compounds: Characterization of Metabolite Profiles and Preliminary Evaluation of Antioxidant Activity

Molecules ◽  
2018 ◽  
Vol 23 (4) ◽  
pp. 725 ◽  
Author(s):  
Dario Donno ◽  
Maria Mellano ◽  
Marta De Biaggi ◽  
Isidoro Riondato ◽  
Ernest Rakotoniaina ◽  
...  
Keyword(s):  
Antioxidant Activity ◽  
Natural Compounds ◽  
Preliminary Evaluation ◽  
Prunus Padus ◽  
New Findings ◽  
Metabolite Profiles

scholarly journals Structures of the surface exposed proteins of Gram positive bacteria

2014 ◽  
Vol 70 (a1) ◽  
pp. C432-C432
Author(s):  
George Minasov ◽  
Salvatore Nocadello ◽  
Ekaterina Filippova ◽  
Andrei Halavaty ◽  
Wayne Anderson
Keyword(s):  
Cell Wall ◽  
Infectious Diseases ◽  
Bacillus Anthracis ◽  
Structural Genomics ◽  
Drug Targets ◽  
Morphological Changes ◽  
Target Selection ◽  
Surface Proteins ◽  
Human Pathogens ◽  
Gram Positive

The Center for Structural Genomics for Infectious Diseases (CSGID) applies structural genomics approaches to biomedically important proteins from human pathogens. It also provides the infectious disease community with a high throughput pipeline for structure determination that carries out all steps of the process, from target selection through structure deposition. Target proteins include drug targets, essential enzymes, virulence factors and vaccine candidates. The CSGID has deposited over 680 structures in the Protein Data Bank. The proteins that are exposed on the surface of Gram positive bacterial pathogens (including Staphylococcus aureus, Bacillus anthracis, Listeria monocytogenes, Streptococcus species and Clostridium species) have been one focus area for the CSGID. So far, the structures of more than 55 of these proteins have been determined. The surface proteins are important in the interactions between the pathogen and its host, but many of them are as yet functionally uncharacterized. Among the examples that will be presented is the Bacillus anthracis SpoIID protein. SpoIID is part of a coordinated cell wall degradation machine that is essential for sporulation and the morphological changes involved. It represents a new family of lytic transglycosylases that degrade the glycan strands of the peptidoglycan cell wall. The two active site clefts in the dimeric enzyme include residues from both subunits, suggesting that the dimer is required for activity. This project has been funded in whole or in part with Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under Contracts No. HHSN272200700058C and HHSN272201200026C.

Developmental gene expression in Leishmania donovani: differential cloning and analysis of an amastigote-stage-specific gene

1994 ◽  
Vol 14 (5) ◽  
pp. 2975-2984
Author(s):  
H Charest ◽  
G Matlashewski
Keyword(s):  
Life Cycle ◽  
Leishmania Donovani ◽  
Repetitive Sequences ◽  
Protozoan Parasite ◽  
Life Cycle Stage ◽  
Immune Serum ◽  
Sand Fly ◽  
Specific Gene ◽  
Reading Frame ◽  
Developmental Gene Expression

Leishmania protozoans are the causative agents of leishmaniasis, a major parasitic disease in humans. During their life cycle, Leishmania protozoans exist as flagellated promastigotes in the sand fly vector and as nonmotile amastigotes in the mammalian hosts. The promastigote-to-amastigote transformation occurs in the phagolysosomal compartment of the macrophage cell and is a critical step for the establishment of the infection. To study this cytodifferentiation process, we differentially screened an amastigote cDNA library with life cycle stage-specific cDNA probes and isolated seven cDNAs representing amastigote-specific transcripts. Five of these were closely related (A2 series) and recognized, by Northern (RNA) blot analyses, a 3.5-kb transcript in amastigotes and in amastigote-infected macrophages. Expression of the amastigote-specific A2 gene was induced in promastigotes when they were transferred from culture medium at 26 degrees C and pH 7.4 to medium at 37 degrees C and pH 4.5, conditions which mimic the macrophage phagolysosomal environment. A2 genes are clustered in tandem arrays, and a 6-kb fragment corresponding to a unit of the cluster was cloned and partially sequenced. An open reading frame found within the A2-transcribed region potentially encoded a 22-kDa protein containing repetitive sequences. The recombinant A2 protein produced in Escherichia coli cells was specifically recognized by immune serum from a patient with visceral leishmaniasis. The A2 protein repetitive element has strong homology with an S antigen of Plasmodium falciparum, the protozoan parasite responsible for malaria. Both the A2 protein of Leishmania donovani and the S antigen of P. falciparum are stage specific and developmentally expressed in mammalian hosts.

The transcriptome of Echinostoma caproni adults: Further characterization of the secretome and identification of new potential drug targets

2013 ◽  
Vol 89 ◽  
pp. 202-214 ◽  
Author(s):  
Gagan Garg ◽  
Dolores Bernal ◽  
Maria Trelis ◽  
Javier Forment ◽  
Javier Ortiz ◽  
...  
Keyword(s):  
Drug Targets ◽  
Potential Drug ◽  
Echinostoma Caproni ◽  
Potential Drug Targets

scholarly journals Genomic and phenotypic characterization of experimentally selected resistant Leishmania donovani reveals a role for dynamin-1 like protein in the mechanism of resistance to a novel anti-leishmanial compound

2021 ◽  
Author(s):  
Aya Hefnawy ◽  
Gabriel Negreira ◽  
Marlene Jara ◽  
James A. Cotton ◽  
Ilse Maes ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Visceral Leishmaniasis ◽  
Infectious Diseases ◽  
Leishmania Donovani ◽  
Neglected Tropical Diseases ◽  
Arms Race ◽  
Etiological Agent ◽  
Phenotypic Characterization ◽  
Tropical Diseases

AbstractThe implementation of prospective drug resistance (DR) studies in the R&D pipelines is a common practice for many infectious diseases, but not for Neglected Tropical Diseases. Here, we explored and demonstrated the importance of this approach, using as paradigms Leishmania donovani, the etiological agent of Visceral Leishmaniasis (VL), and TCMDC-143345, a promising compound of the GSK ‘Leishbox’ to treat VL. We experimentally selected resistance to TCMDC-143345 in vitro and characterized resistant parasites at genomic and phenotypic levels. We found that it took more time to develop resistance to TCMDC-143345 than to other drugs in clinical use and that there was no cross resistance to these drugs, suggesting a new and unique mechanism. By whole genome sequencing, we found two mutations in the gene encoding the L. donovani dynamin-1-like protein (LdoDLP1) that were fixed at highest drug pressure. Through phylogenetic analysis, we identified LdoDLP1 as a family member of the dynamin-related proteins, a group of proteins that impacts the shapes of biological membranes by mediating fusion and fission events, with a putative role in mitochondrial fission. We found that L. donovani lines genetically engineered to harbor the two identified LdoDLP1 mutations were resistant to TCMDC-143345 and displayed altered mitochondrial properties. By homology modeling, we showed how the two LdoDLP1 mutations may influence protein structure and function. Taken together, our data reveal a clear involvement of LdoDLP1 in the adaptation/resistance of L. donovani to TCMDC-143345.ImportanceHumans and their pathogens are continuously locked in a molecular arms race during which the eventual emergence of pathogen drug resistance (DR) seems inevitable. For neglected tropical diseases (NTDs), DR is generally studied retrospectively, once it has already been established in clinical settings. We previously recommended to keep one step ahead in the host-pathogen arms race and implement prospective DR studies in the R&D pipeline, a common practice for many infectious diseases, but not for NTDs. Here, using Leishmania donovani, the etiological agent of Visceral Leishmaniasis (VL), and TCMDC-143345, a promising compound of the GSK ‘Leishbox’ to treat VL, as paradigms, we experimentally selected resistance to the compound and proceeded to genomic and phenotypic characterization of DR parasites. The results gathered in the present study suggest a new DR mechanism involving the L. donovani dynamin-1 like protein (LdoDLP1) and demonstrate the practical relevance of prospective DR studies.

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