scholarly journals From Prokaryotes to Eukaryotes: Insights Into the Molecular Structure of Glycogen Particles

2021 ◽  
Vol 8 ◽  
Author(s):  
Qing-Hua Liu ◽  
Jia-Wei Tang ◽  
Peng-Bo Wen ◽  
Meng-Meng Wang ◽  
Xiao Zhang ◽  
...  
Keyword(s):  
Molecular Structure ◽  
Drug Targets ◽  
Analytical Techniques ◽  
Model Organisms ◽  
Human Beings ◽  
Associated Proteins ◽  
Blood Glucose Homeostasis ◽  
Treatment Of Diabetes ◽  
Novel Drug ◽  
Glycogen Particles

Glycogen is a highly-branched polysaccharide that is widely distributed across the three life domains. It has versatile functions in physiological activities such as energy reserve, osmotic regulation, blood glucose homeostasis, and pH maintenance. Recent research also confirms that glycogen plays important roles in longevity and cognition. Intrinsically, glycogen function is determined by its structure that has been intensively studied for many years. The recent association of glycogen α-particle fragility with diabetic conditions further strengthens the importance of glycogen structure in its function. By using improved glycogen extraction procedures and a series of advanced analytical techniques, the fine molecular structure of glycogen particles in human beings and several model organisms such as Escherichia coli, Caenorhabditis elegans, Mus musculus, and Rat rattus have been characterized. However, there are still many unknowns about the assembly mechanisms of glycogen particles, the dynamic changes of glycogen structures, and the composition of glycogen associated proteins (glycogen proteome). In this review, we explored the recent progresses in glycogen studies with a focus on the structure of glycogen particles, which may not only provide insights into glycogen functions, but also facilitate the discovery of novel drug targets for the treatment of diabetes mellitus.

scholarly journals Identification of novel drug targets using model organisms

2009 ◽  
Vol 30 (2) ◽  
pp. 95
Author(s):  
Anthony Brzoska ◽  
Ryan Withers ◽  
Kylie Turner ◽  
Andrew Robinson ◽  
Nick Dizon ◽  
...  
Keyword(s):  
Drug Targets ◽  
Acquired Resistance ◽  
New Drugs ◽  
Model Organisms ◽  
Magic Bullet ◽  
The Public ◽  
Vancomycin Resistant ◽  
Novel Drug ◽  
General Community ◽  
Novel Drug Targets

Antibiotic resistance is an endemic problem within hospitals worldwide, and is becoming an increasing problem within the general community. Traditionally, physicians and the public have relied on the belief that as bacteria acquired resistance to one antibiotic, new drugs would be made available that could be used to combat those infections. The appearance of vancomycin-resistant Enterococcus (VRE) infections in the 1990s, combined with the withdrawal of funding for antimicrobial drug discovery and development by big Pharma, has led to the realisation that we can no longer assume that all infections can be treated with a ?magic bullet?. Recent years have seen the emergence of infections that are resistant to all clinically available antibiotics, including newly released drugs such as tigecycline. The cupboard is bare. Or at least it is heading that way.

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 4E Interacting Protein as a Potential Novel Drug Target for Nucleoside Analogues in Trypanosoma Brucei

2021 ◽  
Vol 9 (4) ◽  
pp. 826
Author(s):  
Dorien Mabille ◽  
Camila Cardoso Santos ◽  
Rik Hendrickx ◽  
Mathieu Claes ◽  
Peter Takac ◽  
...  
Keyword(s):  
Mode Of Action ◽  
Drug Target ◽  
Drug Targets ◽  
De Novo ◽  
Treatment Options ◽  
Adenosine Kinase ◽  
Nucleoside Analogues ◽  
Purine Salvage ◽  
Interacting Protein ◽  
Novel Drug

Human African trypanosomiasis is a neglected parasitic disease for which the current treatment options are quite limited. Trypanosomes are not able to synthesize purines de novo and thus solely depend on purine salvage from the host environment. This characteristic makes players of the purine salvage pathway putative drug targets. The activity of known nucleoside analogues such as tubercidin and cordycepin led to the development of a series of C7-substituted nucleoside analogues. Here, we use RNA interference (RNAi) libraries to gain insight into the mode-of-action of these novel nucleoside analogues. Whole-genome RNAi screening revealed the involvement of adenosine kinase and 4E interacting protein into the mode-of-action of certain antitrypanosomal nucleoside analogues. Using RNAi lines and gene-deficient parasites, 4E interacting protein was found to be essential for parasite growth and infectivity in the vertebrate host. The essential nature of this gene product and involvement in the activity of certain nucleoside analogues indicates that it represents a potential novel drug target.

scholarly journals Sirtuin 1 and Sirtuin 3 in Granulosa Cell Tumors

2021 ◽  
Vol 22 (4) ◽  
pp. 2047
Author(s):  
Nina Schmid ◽  
Kim-Gwendolyn Dietrich ◽  
Ignasi Forne ◽  
Alexander Burges ◽  
Magdalena Szymanska ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Granulosa Cell ◽  
Granulosa Cells ◽  
Drug Targets ◽  
Growth Regulation ◽  
Sirtuin 1 ◽  
Ki 67 ◽  
Granulosa Cell Tumors ◽  
Novel Drug

Sirtuins (SIRTs) are NAD+-dependent deacetylases that regulate proliferation and cell death. In the human ovary, granulosa cells express sirtuin 1 (SIRT1), which has also been detected in human tumors derived from granulosa cells, i.e., granulosa cell tumors (GCTs), and in KGN cells. KGN cells are an established cellular model for the majority of GCTs and were used to explore the role of SIRT1. The SIRT1 activator SRT2104 increased cell proliferation. By contrast, the inhibitor EX527 reduced cell numbers, without inducing apoptosis. These results were supported by the outcome of siRNA-mediated silencing studies. A tissue microarray containing 92 GCTs revealed nuclear and/or cytoplasmic SIRT1 staining in the majority of the samples, and also, SIRT2-7 were detected in most samples. The expression of SIRT1–7 was not correlated with the survival of the patients; however, SIRT3 and SIRT7 expression was significantly correlated with the proliferation marker Ki-67, implying roles in tumor cell proliferation. SIRT3 was identified by a proteomic analysis as the most abundant SIRT in KGN. The results of the siRNA-silencing experiments indicate involvement of SIRT3 in proliferation. Thus, several SIRTs are expressed by GCTs, and SIRT1 and SIRT3 are involved in the growth regulation of KGN. If transferable to GCTs, these SIRTs may represent novel drug targets.

scholarly journals Mutation ofRv2887, amarR-Like Gene, Confers Mycobacterium tuberculosis Resistance to an Imidazopyridine-Based Agent

2015 ◽  
Vol 59 (11) ◽  
pp. 6873-6881 ◽  
Author(s):  
Kathryn Winglee ◽  
Shichun Lun ◽  
Marco Pieroni ◽  
Alan Kozikowski ◽  
William Bishai
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Drug Targets ◽  
Efflux Pump ◽  
Transcriptional Regulator ◽  
Cross Resistance ◽  
Loss Of Function ◽  
Strong Activity ◽  
Content Type ◽  
Novel Drug

ABSTRACTDrug resistance is a major problem inMycobacterium tuberculosiscontrol, and it is critical to identify novel drug targets and new antimycobacterial compounds. We have previously identified an imidazo[1,2-a]pyridine-4-carbonitrile-based agent, MP-III-71, with strong activity againstM. tuberculosis. In this study, we evaluated mechanisms of resistance to MP-III-71. We derived three independentM. tuberculosismutants resistant to MP-III-71 and conducted whole-genome sequencing of these mutants. Loss-of-function mutations inRv2887were common to all three MP-III-71-resistant mutants, and we confirmed the role ofRv2887as a gene required for MP-III-71 susceptibility using complementation. The Rv2887 protein was previously unannotated, but domain and homology analyses suggested it to be a transcriptional regulator in the MarR (multiple antibiotic resistance repressor) family, a group of proteins first identified inEscherichia colito negatively regulate efflux pumps and other mechanisms of multidrug resistance. We found that two efflux pump inhibitors, verapamil and chlorpromazine, potentiate the action of MP-III-71 and that mutation ofRv2887abrogates their activity. We also used transcriptome sequencing (RNA-seq) to identify genes which are differentially expressed in the presence and absence of a functional Rv2887 protein. We found that genes involved in benzoquinone and menaquinone biosynthesis were repressed by functional Rv2887. Thus, inactivating mutations ofRv2887, encoding a putative MarR-like transcriptional regulator, confer resistance to MP-III-71, an effective antimycobacterial compound that shows no cross-resistance to existing antituberculosis drugs. The mechanism of resistance ofM. tuberculosisRv2887mutants may involve efflux pump upregulation and also drug methylation.

Developing novel chemical entities for the treatment of lysosomal storage disorders: an academic perspective

2015 ◽  
Vol 309 (12) ◽  
pp. F996-F999 ◽  
Author(s):  
James A. Shayman
Keyword(s):  
Drug Targets ◽  
Lysosomal Storage ◽  
Federal Drug Administration ◽  
Drug Candidates ◽  
Gaucher Disease Type 1 ◽  
Biotechnology Companies ◽  
Approved Drugs ◽  
Novel Drug ◽  
Early Drug

Historically, most Federal Drug Administration-approved drugs were the result of “in-house” efforts within large pharmaceutical companies. Over the last two decades, this paradigm has steadily shifted as the drug industry turned to startups, small biotechnology companies, and academia for the identification of novel drug targets and early drug candidates. This strategic pivot has created new opportunities for groups less traditionally associated with the creation of novel therapeutics, including small academic laboratories, for engagement in the drug discovery process. A recent example of the successful development of a drug that had its origins in academia is eliglustat tartrate, an oral agent for Gaucher disease type 1.

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