scholarly journals γBOriS: Identification of Origins of Replication in Gammaproteobacteria using Motif-based Machine Learning

2019 ◽  
Author(s):  
Theodor Sperlea ◽  
Lea Muth ◽  
Roman Martin ◽  
Christoph Weigel ◽  
Torsten Waldminghaus ◽  
...  
Keyword(s):  
Machine Learning ◽  
Drug Targets ◽  
Chromosome Replication ◽  
Bacterial Cells ◽  
Origin Of Replication ◽  
Antibiotic Development ◽  
Origins Of Replication ◽  
Novel Drug ◽  
Circular Chromosomes ◽  
Novel Drug Targets

The biology of bacterial cells is, in general, based on the information encoded on circular chromosomes. Regulation of chromosome replication is an essential process which mostly takes place at the origin of replication (oriC). Identification of high numbers of oriC is a prerequisite to enable systematic studies that could lead to insights of oriC functioning as well as novel drug targets for antibiotic development. Current methods for identyfing oriC sequences rely on chromosome-wide nucleotide disparities and are therefore limited to fully sequenced genomes, leaving a superabundance of genomic fragments unstudied. Here, we present γBOriS (Gammaproteobacterial oriCSearcher), which accurately identifies oriC sequences on gammaproteobacterial chromosomal fragments by employing motif-based DNA classification. Using γBOriS, we created BOriS DB, which currently contains 25,827 oriC sequences from 1,217 species, thus making it the largest available database for oriC sequences to date.

scholarly journals Blocking the Trigger: Inhibition of the Initiation of Bacterial Chromosome Replication as an Antimicrobial Strategy

Antibiotics ◽  
2019 ◽  
Vol 8 (3) ◽  
pp. 111
Author(s):  
Julia E. Grimwade ◽  
Alan C. Leonard
Keyword(s):  
Drug Targets ◽  
Antimicrobial Agents ◽  
Current Knowledge ◽  
Chromosome Replication ◽  
Bacterial Chromosome ◽  
Resistant Bacteria ◽  
Bacterial Cells ◽  
Drug Resistant Bacteria ◽  
New Antibiotics ◽  
Novel Drug

All bacterial cells must duplicate their genomes prior to dividing into two identical daughter cells. Chromosome replication is triggered when a nucleoprotein complex, termed the orisome, assembles, unwinds the duplex DNA, and recruits the proteins required to establish new replication forks. Obviously, the initiation of chromosome replication is essential to bacterial reproduction, but this process is not inhibited by any of the currently-used antimicrobial agents. Given the urgent need for new antibiotics to combat drug-resistant bacteria, it is logical to evaluate whether or not unexploited bacterial processes, such as orisome assembly, should be more closely examined for sources of novel drug targets. This review will summarize current knowledge about the proteins required for bacterial chromosome initiation, as well as how orisomes assemble and are regulated. Based upon this information, we discuss current efforts and potential strategies and challenges for inhibiting this initiation pharmacologically.

Novel drug targets in 2019

2020 ◽  
Vol 19 (5) ◽  
pp. 300-300 ◽  
Author(s):  
Sorin Avram ◽  
Liliana Halip ◽  
Ramona Curpan ◽  
Tudor I. Oprea
Keyword(s):  
Drug Targets ◽  
Novel Drug ◽  
Novel Drug Targets

scholarly journals Identification of Polo-like kinases as potential novel drug targets for influenza A virus

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Marie O. Pohl ◽  
Jessica von Recum-Knepper ◽  
Ariel Rodriguez-Frandsen ◽  
Caroline Lanz ◽  
Emilio Yángüez ◽  
...  
Keyword(s):  
Influenza A Virus ◽  
Drug Targets ◽  
Influenza A ◽  
Novel Drug ◽  
Novel Drug Targets

scholarly journals Utilizing Functional Genomics Screening to Identify Potentially Novel Drug Targets in Cancer Cell Spheroid Cultures

10.3791/54738 ◽  
2016 ◽  
Author(s):  
Eamonn Morrison ◽  
Patty Wai ◽  
Andri Leonidou ◽  
Philip Bland ◽  
Saira Khalique ◽  
...  
Keyword(s):  
Functional Genomics ◽  
Cancer Cell ◽  
Drug Targets ◽  
Cell Spheroid ◽  
Novel Drug ◽  
Novel Drug Targets

scholarly journals Multi-omics data integration reveals novel drug targets in hepatocellular carcinoma

BMC Genomics ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Christos Dimitrakopoulos ◽  
Sravanth Kumar Hindupur ◽  
Marco Colombi ◽  
Dritan Liko ◽  
Charlotte K. Y. Ng ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Drug Targets ◽  
Mtor Signaling ◽  
Omics Data ◽  
Genetic Changes ◽  
Genetic Aberrations ◽  
Functional Consequences ◽  
Novel Drug ◽  
Novel Drug Targets ◽  
Omics Data Integration

Abstract Background Genetic aberrations in hepatocellular carcinoma (HCC) are well known, but the functional consequences of such aberrations remain poorly understood. Results Here, we explored the effect of defined genetic changes on the transcriptome, proteome and phosphoproteome in twelve tumors from an mTOR-driven hepatocellular carcinoma mouse model. Using Network-based Integration of multi-omiCS data (NetICS), we detected 74 ‘mediators’ that relay via molecular interactions the effects of genetic and miRNA expression changes. The detected mediators account for the effects of oncogenic mTOR signaling on the transcriptome, proteome and phosphoproteome. We confirmed the dysregulation of the mediators YAP1, GRB2, SIRT1, HDAC4 and LIS1 in human HCC. Conclusions This study suggests that targeting pathways such as YAP1 or GRB2 signaling and pathways regulating global histone acetylation could be beneficial in treating HCC with hyperactive mTOR signaling.

Abstract P283: CCL5 Acts As A Vasoconstrictor On Penetrating Arterioles In The Cerebral Circulation By Enhancing 20-HETE Activity

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Reece F Crumpler ◽  
Huawei Zhang ◽  
Xing Fang ◽  
Shaoxun Wang ◽  
Baoying Zheng ◽  
...  
Keyword(s):  
Drug Targets ◽  
Perfusion Pressure ◽  
Synthesis Inhibitor ◽  
Atherosclerosis Risk In Communities ◽  
Cyp Enzymes ◽  
Sd Rats ◽  
Sodium Regulation ◽  
Novel Drug ◽  
The Brain ◽  
Novel Drug Targets

20-HETE is synthesized from arachidonic acid by cytochrome P450 (CYP) enzymes 4A and 4F. Inactivating mutations in the CYP enzymes that produce 20-HETE are associated with hypertension and stroke in man. We previously revealed that inactivating variants of CYP4A/F enzymes are associated with dementia in the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NS) population. 20-HETE is involved with sodium regulation in the kidney and is a powerful vasoconstrictor. It was recently discovered that CCL5 and 20-HETE share the same receptor, GPR75. We previously found that 20-HETE constricts and augments the myogenic response (MR) of the middle cerebral artery (MCA) and renal afferent arteriole. However, whether CCL5 has any effect on penetrating arterioles (PAs) and interacts with 20-HETE is unknown. We found that GPR75 is expressed in PAs and pericytes in the brain. CYP4A is also expressed in pericytes and is inversely proportional to levels of GPR75 in the brain. In the present study, we found that 20-HETE contributes to the basal myogenic tone of PAs in SD rats. Administration of HET0016, a 20-HETE synthesis inhibitor, dilated the PA by 34 ± 3% (n = 6) under 10 mmHg perfusion pressure. Administration of WIT003, a 20-HETE agonist, constricted the vessel by 23 ± 4% (n = 6) under the same perfusion pressure. We found that CCL5 also reduced PA diameter by 20 ± 4% (n = 7) in SD rats under 10 mmHg perfusion pressure. Moreover, we compared the response to CCL5 in SS rats that are 20-HETE deficient and SS.CYP4A1 transgenic rats in which 20-HETE production is restored. PAs isolated from SS rats treated with 0.1 nM CCL5 constricted by 9 ± 5% (n = 6) while those treated with 10 nM constricted by 12 ± 3% (n = 6). CCL5 had a greater response in PAs from the SS.CYP4A1 strain, and the diameter of the PAs constricted by 14 ± 2% (n = 5) and 24 ± 5% (n = 5) in response to 0.1 and 10 nM CCL5, respectively. These results demonstrate that CCL5 has a direct effect on PAs similar to 20-HETE that acts via the GPR75 receptor. However, further study is needed to determine how CCL5 and 20-HETE interact to promote vasoconstriction. These studies would help further understand the involvement of 20-HETE in disease and potentially identify novel drug targets.

Targettri: A toxicity-based triaging system for novel drug targets

2018 ◽  
Vol 93 ◽  
pp. 143
Author(s):  
Jennifer Venhorst ◽  
Eugene P. van Someren ◽  
Fred J. van de Brug ◽  
Gino J. Kalkman ◽  
Simon Folkertsma
Keyword(s):  
Drug Targets ◽  
Novel Drug ◽  
Novel Drug Targets
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