Prediction of Novel Drug Targets and Vaccine Candidates against Human Lice (Insecta), Acari (Arachnida), and Their Associated Pathogens

The emergence of drug-resistant lice, acari, and their associated pathogens (APs) is associated with economic losses; thus, it is essential to find new appropriate therapeutic approaches. In the present study, a subtractive proteomics approach was used to predict suitable therapeutics against these vectors and their infectious agents. We found 9701 proteins in the lice (Pediculus humanus var. corporis) and acari (Ixodes scapularis, Leptotrombidium deliense), and 4822 proteins in the proteomes of their APs (Babesia microti, Borreliella mayonii, Borrelia miyamotoi, Borrelia recurrentis, Rickettsia prowazekii, Orientia tsutsugamushi str. Boryong) that were non-homologous to host proteins. Among these non-homologous proteins, 365 proteins of lice and acari, and 630 proteins of APs, were predicted as essential proteins. Twelve unique essential proteins were predicted to be involved in four unique metabolic pathways of lice and acari, and 103 unique proteins were found to be involved in 75 unique metabolic pathways of APs. The sub cellular localization analysis of 115 unique essential proteins of lice and acari and their APs revealed that 61 proteins were cytoplasmic, 42 as membrane-bound proteins and 12 proteins with multiple localization. The druggability analysis of the identified 73 cytoplasmic and multiple localization essential proteins revealed 22 druggable targets and 51 novel drug targets that participate in unique pathways of lice and acari and their APs. Further, the predicted 42 membrane bound proteins could be potential vaccine candidates. Screening of useful inhibitors against these novel targets may result in finding novel compounds efficient for the control of these parasites.

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IN SILICO IDENTIFICATION OF NOVEL DRUG TARGETS IN ACINETOBACTER BAUMANNII BY SUBTRACTIVE GENOMIC APPROACH

Asian Journal of Pharmaceutical and Clinical Research ◽

10.22159/ajpcr.2018.v11i3.22105 ◽

2018 ◽

Vol 11 (3) ◽

pp. 230 ◽

Cited By ~ 3

Author(s):

Meenu Goyal ◽

Citu Citu ◽

Nidhi Singh

Keyword(s):

Acinetobacter Baumannii ◽

In Silico ◽

Metabolic Pathways ◽

Drug Targets ◽

Potential Drug ◽

Homologous Proteins ◽

Essential Proteins ◽

Novel Drug ◽

Potential Drug Targets ◽

Novel Drug Targets

Objective: Multiple drug resistance (MDR) in bacteria, particularly Gram-negative bacilli, has significantly hindered the treatment of infections caused by these bacteria. This results in the need for identifying new drugs and drug targets for these bacteria. The objective of this study was to identify novel drug targets in Acinetobacter baumannii which has emerged as a medically important pathogen due to an increasing number of infections caused by it and its MDR property.Methods: In our study, we implemented in silico subtractive genomics approach to identify novel drug targets in A. baumannii American type culture collection 17978. Various databases and online software were used to build a systematic workflow involving comparative genomics, metabolic pathways analysis, and drug target prioritization to identify pathogen-specific novel drug targets.Results: First, 458 essential proteins were retrieved from a database of essential genes, and by performing BLASTp against Homo sapiens, 246 human non-homologous essential proteins were selected of 458 proteins. Metabolic pathway analysis performed by Kyoto Encyclopedia of Genes and Genomes–Kyoto Automatic Annotation Server revealed that these 246 essential non-homologous proteins were involved in 66 metabolic pathways. Among these metabolic pathways, 12 pathways were found to be unique to Acinetobacter that involved 37 non-homologous essential proteins. Of these essential non-homologous proteins, 19 proteins were found in common as well as unique metabolic pathways and only 18 proteins were unique to Acinetobacter. Finally, these target proteins were filtered to 9 potential targets, based on subcellular localization and assessment of druggability using Drug bank, ChEMBL, and literature.Conclusion: Our study identified nine potential drug targets which are novel targets in A. baumannii and can be used for designing drugs against these proteins. These drugs will be pathogen specific with no side effects on human host, as the potential drug targets are human non-homologous.

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Modeling Novel Putative Drugs and Vaccine Candidates against Tick-Borne Pathogens: A Subtractive Proteomics Approach

Veterinary Sciences ◽

10.3390/vetsci7030129 ◽

2020 ◽

Vol 7 (3) ◽

pp. 129

Author(s):

Abid Ali ◽

Shabir Ahmad ◽

Abdul Wadood ◽

Ashfaq U. Rehman ◽

Hafsa Zahid ◽

...

Keyword(s):

Drug Targets ◽

Effective Control ◽

Potential Drug ◽

Homologous Proteins ◽

Vaccine Candidates ◽

Target Proteins ◽

Subtractive Proteomics ◽

Novel Drug ◽

Potential Drug Targets ◽

Novel Drug Targets

Ticks and tick-borne pathogens (TBPs) continuously causing substantial losses to the public and veterinary health sectors. The identification of putative drug targets and vaccine candidates is crucial to control TBPs. No information has been recorded on designing novel drug targets and vaccine candidates based on proteins. Subtractive proteomics is an in silico approach that utilizes extensive screening for the identification of novel drug targets or vaccine candidates based on the determination of potential target proteins available in a pathogen proteome that may be used effectively to control diseases caused by these infectious agents. The present study aimed to investigate novel drug targets and vaccine candidates by utilizing subtractive proteomics to scan the available proteomes of TBPs and predict essential and non-host homologous proteins required for the survival of these diseases causing agents. Subtractive proteome analysis revealed a list of fifteen essential, non-host homologous, and unique metabolic proteins in the complete proteome of selected pathogens. Among these therapeutic target proteins, three were excluded due to the presence in host gut metagenome, eleven were found to be highly potential drug targets, while only one was found as a potential vaccine candidate against TBPs. The present study may provide a foundation to design potential drug targets and vaccine candidates for the effective control of infections caused by TBPs.

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Reconstruction of Sugar Metabolic Pathways of Giardia lamblia

International Journal of Proteomics ◽

10.1155/2012/980829 ◽

2012 ◽

Vol 2012 ◽

pp. 1-9 ◽

Cited By ~ 8

Author(s):

Jian Han ◽

Lesley J. Collins

Keyword(s):

Giardia Lamblia ◽

Metabolic Pathways ◽

Drug Targets ◽

Sugar Metabolism ◽

Tca Cycle ◽

The Tca Cycle ◽

Glycolysis Pathway ◽

Bioinformatic Approaches ◽

Novel Drug ◽

Novel Drug Targets

Giardia lamblia is an “important” pathogen of humans, but as a diplomonad excavate it is evolutionarily distant from other eukaryotes and relatively little is known about its core metabolic pathways. KEGG, the widely referenced site for providing information of metabolism, does not yet include many enzymes from Giardia species. Here we identify Giardia’s core sugar metabolism using standard bioinformatic approaches. By comparing Giardia proteomes with known enzymes from other species, we have identified enzymes in the glycolysis pathway, as well as some enzymes involved in the TCA cycle and oxidative phosphorylation. However, the majority of enzymes from the latter two pathways were not identifiable, indicating the likely absence of these functionalities. We have also found enzymes from the Giardia glycolysis pathway that appear more similar to those from bacteria. Because these enzymes are different from those found in mammals, the host organisms for Giardia, we raise the possibility that these bacteria-like enzymes could be novel drug targets for treating Giardia infections.

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Subtractive Genomics Approach for Identification of Novel Therapeutic Drug Targets in Mycoplasma genitalium

Pathogens ◽

10.3390/pathogens10080921 ◽

2021 ◽

Vol 10 (8) ◽

pp. 921

Author(s):

Abiodun Joseph Fatoba ◽

Moses Okpeku ◽

Matthew Adekunle Adeleke

Keyword(s):

Metabolic Pathways ◽

Drug Targets ◽

Mycoplasma Genitalium ◽

Therapeutic Drug ◽

Homologous Proteins ◽

Subtractive Genomics ◽

Cytoplasmic Proteins ◽

Novel Drug ◽

Novel Drug Targets ◽

Novel Therapeutic

Mycoplasma genitalium infection is a sexually transmitted infection that causes urethritis, cervicitis, and pelvic inflammatory disease (PID) in men and women. The global rise in antimicrobial resistance against recommended antibiotics for the treatment of M. genitalium infection has triggered the need to explore novel drug targets against this pathogen. The application of a bioinformatics approach through subtractive genomics has proven highly instrumental in predicting novel therapeutic targets against a pathogen. This study aimed to identify essential and non-homologous proteins with unique metabolic pathways in the pathogen that could serve as novel drug targets. Based on this, a manual comparison of the metabolic pathways of M. genitalium and the human host was done, generating nine pathogen-specific metabolic pathways. Additionally, the analysis of the whole proteome of M. genitalium using different bioinformatics databases generated 21 essential, non-homologous, and cytoplasmic proteins involved in nine pathogen-specific metabolic pathways. The further screening of these 21 cytoplasmic proteins in the DrugBank database generated 13 druggable proteins, which showed similarity with FDA-approved and experimental small-molecule drugs. A total of seven proteins that are involved in seven different pathogen-specific metabolic pathways were finally selected as novel putative drug targets after further analysis. Therefore, these proposed drug targets could aid in the design of potent drugs that may inhibit the functionality of these pathogen-specific metabolic pathways and, as such, lead to the eradication of this pathogen.

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Proteome Exploration of Legionella pneumophila for Identifying Novel Therapeutics: A Hierarchical Subtractive Genomics and Reverse Vaccinology Approach

10.1101/2020.02.03.922864 ◽

2020 ◽

Author(s):

Md Tahsin Khan ◽

Araf Mahmud ◽

Mahmudul Hasan ◽

Kazi Faizul Azim ◽

Musammat Kulsuma Begum ◽

...

Keyword(s):

Legionella Pneumophila ◽

Drug Targets ◽

Binding Interaction ◽

Efficient Treatment ◽

Vaccine Candidates ◽

Novel Therapeutics ◽

Mhc Molecules ◽

Subtractive Genomics ◽

Novel Drug ◽

Novel Drug Targets

AbstractLegionella pneumophila, the causative agent of a serious type of pneumonia (lung infection) called Legionnaires’ disease. It is emerging as an antibacterial resistant strain day by day. Hence, the identification of novel drug targets and vaccine candidates is essential to fight against this pathogen. Herein attempts were taken through subtractive genomics approach on complete proteome of L. pneumophila to address the challenges of multidrug resistance. A total 2930 proteins from L. pneumophila proteome were investigated through diverse subtractive proteomics approaches, e.g., identification of human non-homologous and pathogen-specific essential proteins, druggability and ‘anti-target’ analysis, prediction of subcellular localization, human microbiome non-homology screening, protein-protein interactions studies in order to find out effective drug and vaccine targets. Only 3 were identified that fulfilled all these criteria and proposed as novel drug targets against L. pneumophila. Furthermore, outer membrane protein TolB was identified as potential vaccine target with better antigenicity score and allowed for further in silico analysis to design a unique multiepitope subunit vaccine against it. Antigenicity and transmembrane topology screening, allergenicity and toxicity assessment, population coverage analysis, and molecular docking approach were adopted to generate the most potent epitopes. The final vaccine was constructed by the combination of highly immunogenic epitopes along with suitable adjuvant and linkers. The designed vaccine construct showed higher binding interaction with different MHC molecules and human immune TLR2 receptors with minimum deformability at molecular level. The translational potency and microbial expression of the vaccine protein was also analyzed using pET28a(+) vector. The present study aids in the development of novel therapeutics and vaccine candidates for efficient treatment of the infections caused by Legionella pneumophila. However, further wet lab-based investigations and in vivo trials are highly recommended to experimentally validate our prediction.

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