Polymorphisms in Genes of Drug Targets and Metabolism and in DNA Repair

2004 ◽  
pp. 231-243
Author(s):  
Jan Stoehlmacher ◽  
Syma Iqbal ◽  
Heinz-Josef Lenz
Keyword(s):  
Dna Repair ◽  
Drug Targets

scholarly journals Improving Precise CRISPR Genome Editing by Small Molecules: Is there a Magic Potion?

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1318 ◽  
Author(s):  
Nadja Bischoff ◽  
Sandra Wimberger ◽  
Marcello Maresca ◽  
Cord Brakebusch
Keyword(s):  
Gene Therapy ◽  
Dna Repair ◽  
Animal Models ◽  
Molecular Biology ◽  
Small Molecules ◽  
Genome Editing ◽  
Drug Targets ◽  
Targeted Mutagenesis ◽  
Dna Repair Mechanisms ◽  
Repair Mechanisms

Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) genome editing has become a standard method in molecular biology, for the establishment of genetically modified cellular and animal models, for the identification and validation of drug targets in animals, and is heavily tested for use in gene therapy of humans. While the efficiency of CRISPR mediated gene targeting is much higher than of classical targeted mutagenesis, the efficiency of CRISPR genome editing to introduce defined changes into the genome is still low. Overcoming this problem will have a great impact on the use of CRISPR genome editing in academic and industrial research and the clinic. This review will present efforts to achieve this goal by small molecules, which modify the DNA repair mechanisms to facilitate the precise alteration of the genome.

scholarly journals Elucidation of DNA Repair Function of PfBlm and Potentiation of Artemisinin Action by a Small-Molecule Inhibitor of RecQ Helicase

mSphere ◽  
2020 ◽  
Vol 5 (6) ◽  
Author(s):  
Niranjan Suthram ◽  
Siladitya Padhi ◽  
Payal Jha ◽  
Sunanda Bhattacharyya ◽  
Gopalakrishnan Bulusu ◽  
...  
Keyword(s):  
Dna Repair ◽  
Small Molecule ◽  
Economic Burden ◽  
Drug Targets ◽  
Small Molecule Inhibitor ◽  
Morbidity And Mortality ◽  
Effective Vaccine ◽  
Recq Helicase ◽  
Molecule Inhibitor

Malaria continues to be a serious threat to humankind not only because of the morbidity and mortality associated with the disease but also due to the huge economic burden that it imparts. Resistance to all available drugs and the unavailability of an effective vaccine cry for an urgent discovery of newer drug targets.

scholarly journals Proteomic Analysis Directs Effective Drug Selection in Relapsed AML By Quantifying Drug Targets

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5265-5265 ◽  
Author(s):  
David J Britton ◽  
Edmund Wilkes ◽  
Pedro Casado ◽  
Vinothini Rajeeve ◽  
Jude Fitzgibbon ◽  
...  
Keyword(s):  
Dna Repair ◽  
Protein Expression ◽  
Cell Viability ◽  
Cell Lines ◽  
Drug Targets ◽  
Patient Specific ◽  
Protein Drug ◽  
Drug Selection ◽  
Biochemical Pathways ◽  
The Right

Abstract Introduction: Standard therapy for acute myeloid leukaemia (AML) generally includes intense induction with daunorubicin (D) on days 1-3 and cytarabine (A) on days 1-7, followed by consolidation should complete remission (CR) be achieved. Assessment of bone marrow morphology, including percentage of blasts, remains the standard approach to gauge treatment response, however more sensitive molecular based approaches are capable of detecting subclinical levels of leukemic blasts (minimal residual disease, MRD). MRD often remains during and after standard treatment and is the main cause of relapse, a major problem in the management of AML. Resistance of the residual blasts to treatment can be attributed to the activity of pro-survival enzymes, some of which can be pharmacologically inhibited, however, finding the right inhibitor for the right patient presents a major challenge due to the plethora of different enzymes and combinations thereof. Liquid chromatography - tandem mass spectrometry (LC-MS/MS) proteomics enables global and unbiased quantification of protein expression and enzymatic activity in samples. We applied this technology to AML blasts at relapse compared to diagnosis, and in cell lines treated with standard chemotherapy to detect modulated biochemical pathways that contribute to resistance. Thorough investigation into the expression and activity of the protein drug targets enabled selection of inhibitors which proved effective when cells were treated in culture. This approach represents an effective way to better understand the biochemistry of cells following chemotherapy and identify suitable drug targets in biopsies to guide effective inhibitor selection. Methods: LC-MS/MS proteomics and phosphoproteomics was used to investigate global protein expression and kinase activity in primary AML samples at diagnosis and matched relapse (18 cases), and in 3 AML/APL cell lines before and after chemotherapy. Briefly, we collected frozen biopsy specimens from the Barts tissue bank and after thawing the AML blasts were incubated in media for 2 hr at 37oC. Cell lines (HL60, MV411 and P31/FUJ) were treated ± D and/or A (2, 6, or 24 hr). After incubation, cells were centrifuged and washed in PBS, then proteins extracted in urea lysis buffer. Proteins were digested with trypsin, and resulting peptides analysed directly by LC-MS/MS for proteomics or subjected to phosphopeptide enrichment using TiO2 for phosphoproteomics. Commercial (Mascot) and in-house (Pescal, KSEA) software were utilised to identify and quantify proteins, determine kinase activities and investigate intracellular signalling. Cell Viability of blasts ± treatments were recorded using the Guava ViaCount Reagent and Cytometer. Results: On average, >3000 proteins and >9,000 phosphorylation sites were identified per sample. One of the drug targets that correlated strongest with % blasts was CD99 (r=0.79). Blasts showed high abundance & activity of enzymes involved in DNA repair (e.g. PARP1, ATR and PRKDC) at diagnosis and relapse, several significantly increasing in relapse (e.g. PLK3 and APEX1). We observed significant increase in phosphorylation of signalling proteins, such as KIT and STAT5, in relapse. Other signalling pathways regulating survival, apoptosis and metabolism were modulated after relapse but these were patient specific. AML cell lines were more sensitive to D than A. HL60 was the most sensitive cell line while P31/FUJ were least sensitive. Chemotherapy significantly increased the activity of ATM, ATR, PRKDC and MAPKAPK2. Phosphorylation of HSPB1 increased significantly in the presence of D and/or A, and inversely correlated with sensitivity of cells to these drugs. Simultaneous inhibition of ATM & ATR significantly reduced P31/FUJ & MV411 cell viability ± A, while MAPKAPK2 inhibition increased sensitivity of MV411 cells to A. Conclusion: We identified the most abundant and active protein drug targets in AML primary samples and cell lines. Investigating primary AML at diagnosis and relapse uncovered changes in biochemical pathways that regulate DNA repair, survival, apoptosis and metabolism, some of them being modulated by chemotherapy in AML cell lines. These changes were often patient specific, suggesting that to effectively implement targeted therapies, a personalised approach is required and we demonstrate drug selection can be directed by LC-MS/MS proteomics. Disclosures No relevant conflicts of interest to declare.

Focusing on DNA Repair and Damage Tolerance Mechanisms in Mycobacterium tuberculosis: An Emerging Therapeutic Theme

2020 ◽  
Vol 20 (5) ◽  
pp. 390-408 ◽  
Author(s):  
Pooja Mittal ◽  
Rajesh Sinha ◽  
Amit Kumar ◽  
Pooja Singh ◽  
Moses Rinchui Ngasainao ◽  
...  
Keyword(s):  
Dna Repair ◽  
Mycobacterium Tuberculosis ◽  
Drug Targets ◽  
Damage Tolerance ◽  
Patient Adherence ◽  
Drug Regimen ◽  
Drug Resistant ◽  
Long Duration ◽  
Resistant Strains ◽  
Drug Resistant Strains

Tuberculosis (TB) is one such disease that has become a nuisance in the world scenario and one of the most deadly diseases of the current times. The etiological agent of tuberculosis, Mycobacterium tuberculosis (M. tb) kills millions of people each year. Not only 1.7 million people worldwide are estimated to harbor M. tb in the latent form but also 5 to 15 percent of which are expected to acquire an infection during a lifetime. Though curable, a long duration of drug regimen and expense leads to low patient adherence. The emergence of multi-, extensive- and total- drug-resistant strains of M. tb further complicates the situation. Owing to high TB burden, scientists worldwide are trying to design novel therapeutics to combat this disease. Therefore, to identify new drug targets, there is a growing interest in targeting DNA repair pathways to fight this infection. Thus, this review aims to explore DNA repair and damage tolerance as an efficient target for drug development by understanding M. tb DNA repair and tolerance machinery and its regulation, its role in pathogenesis and survival, mutagenesis, and consequently, in the development of drug resistance.

Discovery of Alzheimer's Molecular Pathway Reveals New Drug Targets

ASHA Leader ◽  
2013 ◽  
Vol 18 (3) ◽  
pp. 33-33
Keyword(s):  
Drug Targets ◽  
Molecular Pathway ◽  
New Drug

Discovery of Alzheimer's Molecular Pathway Reveals New Drug Targets

259: Dna-Repair Genetic Polymorphisms and Prostate Cancer Risk

2005 ◽  
Vol 173 (4S) ◽  
pp. 71-71
Author(s):  
Peter E. Clark ◽  
M. Craig Hall ◽  
Kristin L. Lockett ◽  
Jianfeng Xu ◽  
Sigun L. Zheng ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Cancer Risk ◽  
Genetic Polymorphisms ◽  
Prostate Cancer Risk

983: Bladder Cancer Predisposition: A Pathway-Based Approach to DNA Repair and Cell Cycle Control Genes

2006 ◽  
Vol 175 (4S) ◽  
pp. 317-317
Author(s):  
Xifeng Wu ◽  
Jian Gu ◽  
H. Barton Grossman ◽  
Christopher I. Amos ◽  
Carol Etzel ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Bladder Cancer ◽  
Dna Repair ◽  
Cell Cycle Control ◽  
Cancer Predisposition

Drugs Impair Keratinocyte DNA Repair in Culture

2005 ◽  
Vol 36 (7) ◽  
pp. 42
Author(s):  
PATRICE WENDLING
Keyword(s):  
Dna Repair

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
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