Drug targets

Background
Infections caused by Salmonella enterica, a Gram-negative facultative anaerobic bacteria belonging to the family of Enterobacteriaceae, are major threats to the health of humans and animals. The recent availability of complete genome data of pathogenic strains of the S. enterica gives new avenues for the identification of drug targets and drug candidates. We have used the genomic and metabolic pathway data to identify pathways and proteins essential to the pathogen and absent from the host.
Methods
We took the whole proteome sequence data of 42 strains of S. enterica and Homo sapiens along with KEGG-annotated metabolic pathway data, clustered proteins sequences using CD-HIT, identified essential genes using DEG database and discarded S. enterica homologs of human proteins in unique metabolic pathways (UMPs) and characterized hypothetical proteins with SVM-prot and InterProScan. Through this core proteomic analysis we have identified enzymes essential to the pathogen.
Results
The identification of 73 enzymes common in 42 strains of S. enterica is the real strength of the current study.We proposed all 73 unexplored enzymes as potential drug targets against the infections caused by the S. enterica. The study is comprehensive around S. enterica and simultaneously considered every possible pathogenic strain of S. enterica. This comprehensiveness turned the current study significant since, to the best of our knowledge it is the first subtractive core proteomic analysis of the unique metabolic pathways applied to any pathogen for the identification of drug targets. We applied extensive computational methods to shortlist few potential drug targets considering the druggability criteria e.g. Non-homologous to the human host, essential to the pathogen and playing significant role in essential metabolic pathways of the pathogen (i.e. S. enterica). In the current study, the subtractive proteomics through a novel approach was applied i.e. by considering only proteins of the unique metabolic pathways of the pathogens and mining the proteomic data of all completely sequenced strains of the pathogen, thus improving the quality and application of the results. We believe that the sharing of the knowledge from this study would eventually lead to bring about novel and unique therapeutic regimens against the infections caused by the S. enterica.

Heat shock proteins (Hsps) are ubiquitous and
conserved molecules whose main function is to facilitate
protein folding (molecular chaperone function). Some
Hsps such as Hsp70 are also involved in protein folding,
protein trafficking and ubiquitination of misfolded
protein to facilitate their degradation. Hsps occur in functional networks and
hence their coordinated expression is important in
proteostasis. Some Hsps are stress-induced while others
are expressed constitutively. Because of their role as
sentinels of protein folding, it is not surprising that some
Hsps are essential and for this reason, they constitute
potential drug target. However, their high conservation is a snag to their
prospects as drug targets. In spite of this, drugs
targeting some Hsps especially Hsp90 show great
potential and some of them have entered clinical trials
for cancer treatment. In addition,
there are prospects to target Hsps in treatment of
infectious diseases such as malaria

Target discovery using the molecular approach, as opposed to the more traditional systems approach
requires the study of the cellular or biological process underlying a condition or disease. The approaches
that are employed by the “bench” scientist may be genetic, genomic or proteomic and each has its rightful place
in the drug-target discovery process. Affinity-based proteomic techniques currently used in drug-discovery draw upon
several disciplines, synthetic chemistry, cell-biology, biochemistry and mass spectrometry. An important component of
such techniques is the probe that is specifically designed to pick out a protein or set of proteins from amongst the varied
thousands in a cell lysate. A second component, that is just as important, is liquid-chromatography tandem massspectrometry
(LC-MS/MS). LC-MS/MS and the supporting theoretical framework has come of age and is the tool of
choice for protein identification and quantification. These proteomic tools are critical to maintaining the drug-candidate
supply, in the larger context of drug discovery.

The immune system protects a host from foreign pathogens. In rare cases, the immune system can attack the cells of the host organism causing autoimmune diseases. We outline a computational framework that combines bioinformatics and network analysis with an emerging targets platform. The computational framework presented here can be used to find drug targets for autoimmune diseases. It can also be used to find existing drugs that can be repurposed to treat autoimmune diseases based on networks of interactions or similarities between different diseases. Information on which gene regions are associated with the disease (single nucleotide polymorphisms) can be used in gene therapy when that technique becomes viable. Our analysis also revealed immune cell subtypes that are implicated in these diseases. These immune cell subtypes can be selected for immunotherapy experiments. Finally, our analysis also reveals intra-cellular and protein-protein interaction networks and pathways that can be targeted with small molecule inhibitors. The downstream off-target effects of these inhibitors can also be determined from such a network analysis. In summary, our computational framework can be used to find novel therapeutics for autoimmune diseases and potentially even other dysfunctions.

Honey has antioxidant, immunostimulant, antibacterial, and antileishmanial activities. In this study, we evaluated the in vitro babesicidal and theilericidal effects of honey on Babesia bovis, Babesia bigemina, Babesia divergens, Babesia caballi, and Theileria equi. There was noteworthy suppression of growth at a concentration of 0.5% (V/V) for B. bovis, B. bigemina, B. divergens, and T. equi and 1% (V/V) for B. caballi. The IC 50 values of honey were 1.98, 1.82, 0.42, 1.7, and 1.43% (V/V) for B. bovis, B. bigemina, B. divergens, B. caballi, and T. equi, respectively. The growth was entirely repressed at 1% (V/V) for B. divergens, 2.5% (V/V) for T. equi, and 5% (V/V) for B. bovis, B. bigemina, and B. caballi. The regrowth was repressed in the viability test at a concentration of 1% (V/V) for B. divergens, 2.5% (V/V) for T. equi, and 5% (V/V) for B. caballi, B. bovis, and B. bigemina. These results indicate honey as a natural killer of Babesia species and T. equi. Its use in the treatment of clinical cases requires further in vivo evaluation.

An analytical review of the articles published in the two issues of Clinical Immunology Endocrine Metabolic Drugs (volume 1, 2014) is reported. Various topics are covered in volume 1 of the journal. Clinical Immunology is represented in six articles related to nickel hypersensitivity (2 articles), therapeutic approaches in human tuberculosis, immune biomarkers in trauma patients, salivary cytokines in normal weight children and oral sensitization in rats. Endocrinology is the main topic of the two articles dealing with polycystic ovary syndrome and androgen receptor antagonists in prostate cancer. The vascular pathophysiology is the major theme of two papers dealing with the role of angiotensin II and post-prandial oxidative burst. Finally, a paper is devoted to antibiotics resistance of four probiotics.