scholarly journals A New Generation of Minor-Groove-Binding—Heterocyclic Diamidines That Recognize G·C Base Pairs in an AT Sequence Context

Molecules ◽  
2019 ◽  
Vol 24 (5) ◽  
pp. 946 ◽  
Author(s):  
Ananya Paul ◽  
Pu Guo ◽  
David Boykin ◽  
W. Wilson
Keyword(s):  
Base Pair ◽  
Rational Design ◽  
Dna Interaction ◽  
Cell Uptake ◽  
Base Pairs ◽  
Sequence Context ◽  
Simple Change ◽  
New Generation ◽  
New Compounds ◽  
Heterocyclic Cations

We review the preparation of new compounds with good solution and cell uptake properties that can selectively recognize mixed A·T and G·C bp sequences of DNA. Our underlying aim is to show that these new compounds provide important new biotechnology reagents as well as a new class of therapeutic candidates with better properties and development potential than other currently available agents. In this review, entirely different ways to recognize mixed sequences of DNA by modifying AT selective heterocyclic cations are described. To selectively recognize a G·C base pair an H-bond acceptor must be incorporated with AT recognizing groups as with netropsin. We have used pyridine, azabenzimidazole and thiophene-N-methylbenzimidazole GC recognition units in modules crafted with both rational design and empirical optimization. These modules can selectively and strongly recognize a single G·C base pair in an AT sequence context. In some cases, a relatively simple change in substituents can convert a heterocyclic module from AT to GC recognition selectivity. Synthesis and DNA interaction results for initial example lead modules are described for single G·C base pair recognition compounds. The review concludes with a description of the initial efforts to prepare larger compounds to recognize sequences of DNA with more than one G·C base pairs. The challenges and initial successes are described along with future directions.

scholarly journals The Trypanocidal Activity of Amidine Compounds Does Not Correlate with Their Binding Affinity to Trypanosoma cruzi Kinetoplast DNA

2011 ◽  
Vol 55 (10) ◽  
pp. 4765-4773 ◽  
Author(s):  
A. Daliry ◽  
M. Q. Pires ◽  
C. F. Silva ◽  
R. S. Pacheco ◽  
M. Munde ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Cell Uptake ◽  
Kinetoplast Dna ◽  
Content Type ◽  
Trypanocidal Activity ◽  
Cellular Targets ◽  
Conserved Sequence ◽  
Cd Studies ◽  
New Compounds ◽  
Heterocyclic Cations

ABSTRACTDue to limited efficacy and considerable toxicity, the therapy for Chagas' disease is far from being ideal, and thus new compounds are desirable. Diamidines and related compounds such as arylimidamides have promising trypanocidal activity againstTrypanosoma cruzi. To better understand the mechanism of action of these heterocyclic cations, we investigated the kinetoplast DNA (kDNA) binding properties and trypanocidal efficacy againstT. cruziof 13 compounds. Four diamidines (DB75, DB569, DB1345, and DB829), eight arylimidamides (DB766, DB749, DB889, DB709, DB613, DB1831, DB1852, and DB2002), and one guanylhydrazone (DB1080) were assayed in thermal denaturation (Tm) and circular dichroism (CD) studies using whole purifiedT. cruzikDNA and a conserved synthetic parasite sequence. The overall CD spectra using the whole kDNA were similar to those found for the conserved sequence and were indicative of minor groove binding. Our findings showed that some of the compounds that exhibited the highest trypanocidal activities (e.g., DB766) caused low or no change in theTmmeasurements. However, while some active compounds, such as DB766, induced profound alterations of kDNA topology, others, like DB1831, although effective, did not result in alteredTmand CD measurements. Our data suggest that the strong affinity of amidines with kDNAper seis not sufficient to generate and trigger their trypanocidal activity. Cell uptake differences and possibly distinct cellular targets need to be considered in the final evaluation of the mechanisms of action of these compounds.

Detection of the Glanzmann's Thrombasthenia Mutations in Arab and Iraqi-Jewish Patients by Polymerase Chain Reaction and Restriction Analysis of Blood or Urine Samples

1991 ◽  
Vol 66 (04) ◽  
pp. 500-504 ◽  
Author(s):  
H Peretz ◽  
U Seligsohn ◽  
E Zwang ◽  
B S Coller ◽  
P J Newman
Keyword(s):  
Polymerase Chain Reaction ◽  
Base Pair ◽  
Restriction Analysis ◽  
Urine Samples ◽  
Chain Reaction ◽  
Base Pairs ◽  
Glanzmann’S Thrombasthenia ◽  
Glanzmann's Thrombasthenia ◽  
Base Pair Deletion ◽  
Polymerase Chain

SummarySevere Glanzmann's thrombasthenia is relatively frequent in Iraqi-Jews and Arabs residing in Israel. We have recently described the mutations responsible for the disease in Iraqi-Jews – an 11 base pair deletion in exon 12 of the glycoprotein IIIa gene, and in Arabs – a 13 base pair deletion at the AG acceptor splice site of exon 4 on the glycoprotein IIb gene. In this communication we show that the Iraqi-Jewish mutation can be identified directly by polymerase chain reaction and gel electrophoresis. With specially designed oligonucleotide primers encompassing the mutation site, an 80 base pair segment amplified in healthy controls was clearly distinguished from the 69 base pair segment produced in patients. Patients from 11 unrelated Iraqi-Jewish families had the same mutation. The Arab mutation was identified by first amplifying a DNA segment consisting of 312 base pairs in controls and of 299 base pairs in patients, and then digestion by a restriction enzyme Stu-1, which recognizes a site that is absent in the mutant gene. In controls the 312 bp segment was digested into 235 and 77 bp fragments, while in patients there was no change in the size of the amplified 299 bp segment. The mutation was found in patients from 3 out of 5 unrelated Arab families. Both Iraqi-Jewish and Arab mutations were detectable in DNA extracted from blood and urine samples. The described simple methods of identifying the mutations should be useful for detection of the numerous potential carriers among the affected kindreds and for prenatal diagnosis using DNA extracted from chorionic villi samples.

scholarly journals Recent Advancements in Polythiophene-Based Materials and Their Biomedical, Geno Sensor and DNA Detection

2021 ◽  
Vol 22 (13) ◽  
pp. 6850
Author(s):  
Seyyed Mojtaba Mousavi ◽  
Seyyed Alireza Hashemi ◽  
Sonia Bahrani ◽  
Khadije Yousefi ◽  
Gity Behbudi ◽  
...  
Keyword(s):  
Biomedical Engineering ◽  
High Efficiency ◽  
Polymeric Materials ◽  
The Novel ◽  
Electrode Coating ◽  
Effective Response ◽  
Hiv Drugs ◽  
New Generation ◽  
New Compounds ◽  
Anti Hiv

In this review, the unique properties of intrinsically conducting polymer (ICP) in biomedical engineering fields are summarized. Polythiophene and its valuable derivatives are known as potent materials that can broadly be applied in biosensors, DNA, and gene delivery applications. Moreover, this material plays a basic role in curing and promoting anti-HIV drugs. Some of the thiophene’s derivatives were chosen for different experiments and investigations to study their behavior and effects while binding with different materials and establishing new compounds. Many methods were considered for electrode coating and the conversion of thiophene to different monomers to improve their functions and to use them for a new generation of novel medical usages. It is believed that polythiophenes and their derivatives can be used in the future as a substitute for many old-fashioned ways of creating chemical biosensors polymeric materials and also drugs with lower side effects yet having a more effective response. It can be noted that syncing biochemistry with biomedical engineering will lead to a new generation of science, especially one that involves high-efficiency polymers. Therefore, since polythiophene can be customized with many derivatives, some of the novel combinations are covered in this review.

scholarly journals Experimental and theoretical explorations of nanocarriers’ multistep delivery performance for rational design and anticancer prediction

2021 ◽  
Vol 7 (6) ◽  
pp. eaba2458
Author(s):  
Weier Bao ◽  
Falin Tian ◽  
Chengliang Lyu ◽  
Bin Liu ◽  
Bin Li ◽  
...  
Keyword(s):  
Physical Properties ◽  
Rational Design ◽  
Theoretical Models ◽  
Cell Uptake ◽  
Anticancer Efficacy ◽  
Delivery Performance ◽  
Simulation Based ◽  
Multistep Process

The poor understanding of the complex multistep process taken by nanocarriers during the delivery process limits the delivery efficiencies and further hinders the translation of these systems into medicine. Here, we describe a series of six self-assembled nanocarrier types with systematically altered physical properties including size, shape, and rigidity, as well as both in vitro and in vivo analyses of their performance in blood circulation, tumor penetration, cancer cell uptake, and anticancer efficacy. We also developed both data and simulation-based models for understanding the influence of physical properties, both individually and considered together, on each delivery step and overall delivery process. Thus, beyond finding that nanocarriers that are simultaneously endowed with tubular shape, short length, and low rigidity outperformed the other types, we now have a suit of theoretical models that can predict how nanocarrier properties will individually and collectively perform in the multistep delivery of anticancer therapies.

Automation and Management of Design Process of the Main Drive for an Innovative Fruits and Vegetables Washer

2021 ◽  
Vol 27 (1) ◽  
pp. 9-17
Author(s):  
V. P. Bui ◽  
◽  
S. S. Gavruishin ◽  
V. B. Phung ◽  
H. M. Dang ◽  
...  
Keyword(s):  
Design Process ◽  
Rational Design ◽  
Fruits And Vegetables ◽  
Rational Solution ◽  
Quality Criteria ◽  
Pareto Optimal ◽  
Optimal Domain ◽  
Wide Range ◽  
A New Technique ◽  
New Generation

A new technique is described, used by the authors to automate the design process of the main drive of a new generation machine intended for industrial washing of fruits and vegetables. To solve the problem of multi-criteria design, the original approach is proposed that uses interconnected mathematical models describing the dynamic behavior, strength reliability and functional characteristics of the machine in a unified information space. The generalized mathematical model includes 12 controlled parameters, 16 functional constraints, and 3 quality criteria. A genetic algorithm was used to find the space of Pareto-optimal solutions. The situational approach was used to select the final rational solution from a set of solutions belonging to the Pareto-optimal domain. The rational design of option the washer found using the proposed approach is compared with the existing ones. The proposed design methodology can be recommended for the design of a wide range of similar mechanical structures.

Repair of heteroduplex plasmid DNA after transformation into Saccharomyces cerevisiae

1986 ◽  
Vol 6 (10) ◽  
pp. 3401-3409
Author(s):  
D K Bishop ◽  
R D Kolodner
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Plasmid Dna ◽  
Base Pair ◽  
Base Pairs ◽  
Plasmid Dnas ◽  
Repair Efficiency ◽  
Single Insertion ◽  
Base Pair Insertion

Purified heteroduplex plasmid DNAs containing 8- or 12-base-pair insertion mismatches or AC or CT substitution mismatches were used to transform Saccharomyces cerevisiae. Two insertion mismatches, separated by 943 base pairs, were repaired independently of each other at least 55% of the time. This suggested that repair tracts were frequently shorter than 1 kilobase. The two insertion mismatches were repaired with different efficiencies. Comparison of the repair efficiency of one mismatched site with or without an adjacent mismatch suggests that mismatches promote their own repair and can influence the repair of neighboring mismatches. When two different plasmids containing single-insertion mismatches were transformed into S. cerevisiae cells, a slight preference towards insertion was detected among repair products of one of the two plasmids, while no repair preference was detected among transformants with the second plasmid.

scholarly journals Spo0A-Dependent Activation of an Extended −10 Region Promoter in Bacillus subtilis

2006 ◽  
Vol 188 (4) ◽  
pp. 1411-1418 ◽  
Author(s):  
Guangnan Chen ◽  
Amrita Kumar ◽  
Travis H. Wyman ◽  
Charles P. Moran
Keyword(s):  
Bacillus Subtilis ◽  
Base Pair ◽  
Promoter Activity ◽  
Mutational Analysis ◽  
Dna Binding Protein ◽  
Base Pairs ◽  
Dnase I Footprinting ◽  
Level Of Activity ◽  
High Level ◽  
Activity Dependent

ABSTRACT At the onset of endospore formation in Bacillus subtilis the DNA-binding protein Spo0A directly activates transcription from promoters of about 40 genes. One of these promoters, Pskf, controls expression of an operon encoding a killing factor that acts on sibling cells. AbrB-mediated repression of Pskf provides one level of security ensuring that this promoter is not activated prematurely. However, Spo0A also appears to activate the promoter directly, since Spo0A is required for Pskf activity in a ΔabrB strain. Here we investigate the mechanism of Pskf activation. DNase I footprinting was used to determine the locations at which Spo0A bound to the promoter, and mutations in these sites were found to significantly reduce promoter activity. The sequence near the −10 region of the promoter was found to be similar to those of extended −10 region promoters, which contain a TRTGn motif. Mutational analysis showed that this extended −10 region, as well as other base pairs in the −10 region, is required for Spo0A-dependent activation of the promoter. We found that a substitution of the consensus base pair for the nonconsensus base pair at position −9 of Pskf produced a promoter that was active constitutively in both ΔabrB and Δspo0A ΔabrB strains. Therefore, the base pair at position −9 of Pskf makes its activity dependent on Spo0A binding, and the extended −10 region motif of the promoter contributes to its high level of activity.

Three-centre C—H...O hydrogen bonds in the DNA minor groove: analysis of oligonucleotide crystal structures

1999 ◽  
Vol 55 (12) ◽  
pp. 2005-2012 ◽  
Author(s):  
Anirban Ghosh ◽  
Manju Bansal
Keyword(s):  
Hydrogen Bonds ◽  
Crystal Structures ◽  
Base Pair ◽  
Minor Groove ◽  
Local Geometry ◽  
Data Sets ◽  
Base Pairs ◽  
Dna Minor Groove ◽  
Close Proximity ◽  
Using Data

AA·TT and GA·TC dinucleotide steps in B-DNA-type oligomeric crystal structures and in protein-bound DNA fragments (solved using data with resolution <2.6 Å) show very small variations in their local dinucleotide geometries. A detailed analysis of these crystal structures reveals that in AA·TT and GA·TC steps the electropositive C2—H2 group of adenine is in very close proximity to the keto O atoms of both the pyrimidine bases in the antiparallel strand of the duplex structure, suggesting the possibility of intra-base pair as well as cross-strand inter-base pair C—H...O hydrogen bonds in the DNA minor groove. The C2—H2...O2 hydrogen bonds in the A·T base pairs could be a natural consequence of Watson–Crick pairing. However, the cross-strand interactions between the bases at the 3′-end of the AA·TT and GA·TC steps obviously arise owing to specific local geometry of these steps, since a majority of the H2...O2 distances in both data sets are considerably shorter than their values in the uniform fibre model (3.3 Å) and many are even smaller than the sum of the van der Waals radii. The analysis suggests that in addition to already documented features such as the large propeller twist of A·T base pairs and the hydration of the minor groove, these C2—H2...O2 cross-strand interactions may also play a role in the narrowing of the minor groove in A-tract regions of DNA and help explain the high structural rigidity and stability observed for poly(dA)·poly(dT).

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