Browse
Submit Data
Databases
API
Help

Dataset Information

19 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Acid-base and lipophilic properties of peptide nucleic acid derivatives

ABSTRACT: The first combined experimental and theoretical study on the ionization and lipophilic properties of peptide nucleic acid (PNA) derivatives, including eleven PNA monomers and two PNA decamers, is described. The acidity constants (pKa) of individual acidic and basic centers of PNA monomers were measured by automated potentiometric pH titrations in water/methanol solution, and these values were found to be in agreement with those obtained by MoKa software. These results indicate that single nucleobases do not change their pKa values when included in PNA monomers and oligomers. In addition, immobilized artificial membrane chromatography was employed to evaluate the lipophilic properties of PNA monomers and oligomers, which showed the PNA derivatives had poor affinity towards membrane phospholipids, and confirmed their scarce cell penetrating ability. Overall, our study not only is of potential relevance to evaluate the pharmacokinetic properties of PNA, but also constitutes a reliable basis to properly modify PNA to obtain mimics with enhanced cell penetration properties. Graphical abstract Image 1 Highlights • The first study on acid-base and lipophilic properties of peptide nucleic acids (PNA).• pKa of acid-base centers of PNA evaluated by potentiometric method and MoKa prediction.• NMR experiments provide additional information on the protonation of PNA monomers.• Lipophilicity of PNA monomers and oligomers is investigated by IAM chromatography.• This study can lay the basis of evaluating the pharmacokinetic properties of PNA.

SUBMITTER: Thakare P

PROVIDER: S-EPMC8572665 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Pyrrolidinyl peptide nucleic acid with ?/?-peptide backbone: A conformationally constrained PNA with unusual hybridization properties.

Project description:We describe herein a new conformationally constrained analog of PNA carrying an alternating ?/? amino acid backbone consisting of (2'R,4'R)-nucleobase-subtituted proline and (1S,2S)-2-aminocyclopentanecarboxylic acid (acpcPNA). The acpcPNA has been synthesized and evaluated for DNA, RNA and self-pairing properties by thermal denaturation experiments. It can form antiparallel hybrids with complementary DNA with high affinity and sequence specificity. Unlike other PNA systems, the thermal stability of acpcPNA·DNA hybrid is largely independent of G+C contents, and is generally higher than that of acpcPNA·RNA hybrid with the same sequence. Thermodynamic parameters analysis suggest that the A·T base pairs in the acpcPNA·DNA hybrids are enthalpically stabilized over G·C pairs. The acpcPNA also shows a hitherto unreported behavior, namely the inability to form self-pairing hybrids. These unusual properties should make the new acpcPNA a potentially useful candidate for various applications including microarray probes and antigene agents.

| S-EPMC3166490 | biostudies-literature

Formulation of a peptide nucleic acid based nucleic acid delivery construct.

Project description:Gene delivery biomaterials need to be designed to efficiently achieve nuclear delivery of plasmid DNA. Polycations have been used to package DNA and other nucleic acids within submicrometer-sized particles, offering protection from shear-induced or enzymatic degradation. However, cytotoxicity issues coupled with limited in vivo transfection efficiencies minimize the effectiveness of this approach. In an effort to improve upon existing technologies aimed at delivering nucleic acids, an alternative approach to DNA packaging was explored. Peptide nucleic acids (PNAs) were used to directly functionalize DNA with poly(ethylene glycol) (PEG) chains that provide a steric layer and inhibit multimolecular aggregation during complexation. DNA prePEGylation by this strategy was predicted to enable the formation of more homogeneous and efficiently packaged polyplexes. In this work, DNA-PNA-peptide-PEG (DP3) conjugates were synthesized and self-assembled with 25 kDa poly(ethylenimine) (PEI). Complexes with small standard deviations and average diameters ranging 30-50 nm were created, with minimal dependence of complex size on N/P ratio (PEI amines to DNA phosphates). Furthermore, PEI-DNA interactions were altered by the derivatization strategy, resulting in tighter compaction of the PEI-DP3 complexes in comparison to PEI-DNA complexes. Transfection experiments in Chinese hamster ovary (CHO) cells revealed comparable transfection efficiencies but reduced cytotoxicities of the PEI-DP3 complexes relative to PEI-DNA complexes. The enhanced cellular activities of the PEI-DP3 complexes were maintained following the removal of free PEI from the PEI-DP3 formulations, whereas the cellular activity of the conventional PEI-DNA formulations was reduced by free PEI removal. These findings suggest that DNA prePEGylation by the PNA-based strategy might provide a way to circumvent cytotoxicity and formulation issues related to the use of PEI for in vivo gene delivery.

| S-EPMC2891923 | biostudies-literature

Synthesis and optical properties of pyrrolidinyl peptide nucleic acid carrying a clicked Nile red label.

Project description:DNA or its analogues with an environment-sensitive fluorescent label are potentially useful as a probe for studying the structure and dynamics of nucleic acids. In this work, pyrrolidinyl peptide nucleic acid (acpcPNA) was labeled at its backbone with Nile red, a solvatochromic benzophenoxazine dye, by means of click chemistry. The optical properties of the Nile red-labeled acpcPNA were investigated by UV-vis and fluorescence spectroscopy in the absence and in the presence of DNA. In contrast to the usual quenching observed in Nile red-labeled DNA, the hybridization with DNA resulted in blue shifting and an enhanced fluorescence regardless of the neighboring bases. More pronounced blue shifts and fluorescence enhancements were observed when the DNA target carried a base insertion in close proximity to the Nile red label. The results indicate that the Nile red label is located in a more hydrophobic environment in acpcPNA-DNA duplexes than in the single-stranded acpcPNA. The different fluorescence properties of the acpcPNA hybrids of complementary DNA and DNA carrying a base insertion are suggestive of different interactions between the Nile red label and the duplexes.

| S-EPMC4168962 | biostudies-literature

Allele-selective inhibition of mutant huntingtin by peptide nucleic acid-peptide conjugates, locked nucleic acid, and small interfering RNA.

Project description:The ability to inhibit expression of a mutant allele while retaining expression of a wild-type protein might provide a useful approach to treating Huntington's Disease (HD) and other inherited pathologies. The mutant form of huntingtin (HTT), the protein responsible for HD, is encoded by an mRNA containing an expanded CAG repeat. We demonstrate that peptide nucleic acid conjugates and locked nucleic acids complementary to the CAG repeat selectively block expression of mutant HTT. The selectivity of inhibition is at least as good as that shown by a small interfering RNA targeted to a deletion polymorphism. Our data suggest that antisense oligomers are promising subjects for further development as an anti-HD therapeutic strategy.

| S-EPMC3908448 | biostudies-literature

Thermal Stability of Peptide Nucleic Acid Complexes.

Project description:Peptide nucleic acid (PNA) is a neutral nucleic acid analogue that base pairs with itself and natural nucleic acids. PNA-nucleic acid complexes are more thermally stable than the corresponding complexes of natural nucleic acids. In addition, PNA is biostable and thus used in many antisense and antigene applications to block functional RNA or DNA via sequence-specific interactions. We have recently developed force field parameters for molecular dynamics (MD) simulations of PNA and PNA-involving duplexes with natural nucleic acids. In this work, we provide the first application of this force field to biologically relevant PNA sequences and their complexes with RNA. We investigated thermal stabilities of short PNA-PNA, PNA-RNA, and RNA-RNA duplexes using UV-monitored thermal denaturation experiments and MD simulations at ambient and elevated temperatures. The simulations show a two-state melting transition and reproduce the thermal stability from melting experiments, with PNA-PNA being the most and RNA-RNA the least stable. The PNA-PNA duplex also displays the highest activation energy for melting. The atomistic details of unfolding of PNA duplexes suggest that all PNA-PNA bases melt concomitantly, whereas the RNA-RNA and PNA-RNA are destabilized from the termini toward the central part of the duplexes.

| S-EPMC6776699 | biostudies-literature

Perspectives on conformationally constrained peptide nucleic acid (PNA): insights into the structural design, properties and applications.

Project description:Peptide nucleic acid or PNA is a synthetic DNA mimic that contains a sequence of nucleobases attached to a peptide-like backbone derived from N-2-aminoethylglycine. The semi-rigid PNA backbone acts as a scaffold that arranges the nucleobases in a proper orientation and spacing so that they can pair with their complementary bases on another DNA, RNA, or even PNA strand perfectly well through the standard Watson-Crick base-pairing. The electrostatically neutral backbone of PNA contributes to its many unique properties that make PNA an outstanding member of the xeno-nucleic acid family. Not only PNA can recognize its complementary nucleic acid strand with high affinity, but it does so with excellent specificity that surpasses the specificity of natural nucleic acids and their analogs. Nevertheless, there is still room for further improvements of the original PNA in terms of stability and specificity of base-pairing, direction of binding, and selectivity for different types of nucleic acids, among others. This review focuses on attempts towards the rational design of new generation PNAs with superior performance by introducing conformational constraints such as a ring or a chiral substituent in the PNA backbone. A large collection of conformationally rigid PNAs developed during the past three decades are analyzed and compared in terms of molecular design and properties in relation to structural data if available. Applications of selected modified PNA in various areas such as targeting of structured nucleic acid targets, supramolecular scaffold, biosensing and bioimaging, and gene regulation will be highlighted to demonstrate how the conformation constraint can improve the performance of the PNA. Challenges and future of the research in the area of constrained PNA will also be discussed.

| S-EPMC9175113 | biostudies-literature

Digital counting of nucleic acid molecules using random base molecular barcodes

Project description:Several template DNA molecules with random base molecular barcodes were amplified and sequenced, and the efficacy of the random base barcode for digital counting was shown.

2017-10-19 | GSE94895 | GEO

An Improved Reaction Coordinate for Nucleic Acid Base Flipping Studies.

Project description:Base flipping is a common strategy utilized by many enzymes to gain access to the functional groups of nucleic acid bases in duplex DNA which are otherwise protected by the DNA backbone and hydrogen bonding with their partner bases. Several X-ray crystallography studies have revealed flipped conformations of nucleotides bound to enzymes. However, little is known about the base-flipping process itself, even less about the role of the enzymes. Computational studies have used umbrella sampling to elicit the free energy profile of the base-flipping process using a pseudodihedral angle to represent the reaction coordinate. In this study, we have used an unrestrained trajectory in which a flipped base spontaneously reinserted into the helix in order to evaluate and improve the previously defined pseudodihedral angle. Our modified pseudodihedral angles use a new atom selection to improve the numerical stability of the restraints and also provide better correlation to the extent of flipping observed in simulations. Furthermore, on the basis of the comparison of potential of mean force (PMF) generated using different reaction coordinates, we observed that the shape of a flipping PMF profile is strongly dependent on the definition of the reaction coordinate, even for the same data set.

| S-EPMC5442445 | biostudies-literature

Templated synthesis of peptide nucleic acids via sequence-selective base-filling reactions.

Project description:The templated synthesis of nucleic acids has previously been achieved through the backbone ligation of preformed nucleotide monomers or oligomers. In contrast, here we demonstrate templated nucleic acid synthesis using a base-filling approach in which individual bases are added to abasic sites of a peptide nucleic acid (PNA). Because nucleobase substrates in this approach are not self-reactive, a base-filling approach may reduce the formation of nontemplated reaction products. Using either reductive amination or amine acylation chemistries, we observed efficient and selective addition of each of the four nucleobases to an abasic site in the middle of the PNA strand. We also describe the addition of single nucleobases to the end of a PNA strand through base filling, as well as the tandem addition of two bases to the middle of the PNA strand. These findings represent an experimental foundation for nonenzymatic information transfer through base filling.

| S-EPMC2726731 | biostudies-literature

Potent antibacterial antisense peptide-peptide nucleic acid conjugates against Pseudomonas aeruginosa.

Project description:Pseudomonas aeruginosa is an opportunistic pathogen causing severe infections in hospital settings, especially with immune compromised patients, and the increasing prevalence of multidrug resistant strains urges search for new drugs with novel mechanisms of action. In this study we introduce antisense peptide-peptide nucleic acid (PNA) conjugates as antibacterial agents against P. aeruginosa. We have designed and optimized antisense peptide-PNA conjugates targeting the translation initiation region of the ftsZ gene (an essential bacterial gene involved in cell division) or the acpP gene (an essential bacterial gene involved in fatty acid synthesis) of P. aeruginosa (PA01) and characterized these compounds according to their antimicrobial activity and mode of action. Four antisense PNA oligomers conjugated to the H-(R-Ahx-R)(4)-Ahx-?ala or the H-(R-Ahx)(6)-?ala peptide exhibited complete growth inhibition of P. aeruginosa strains PA01, PA14, and LESB58 at 1-2 ?M concentrations without any indication of bacterial membrane disruption (even at 20 ?M), and resulted in specific reduction of the targeted mRNA levels. One of the four compounds showed clear bactericidal activity while the other significantly reduced bacterial survival. These results open the possibility of development of antisense antibacterials for treatment of Pseudomonas infections.

| S-EPMC3464458 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data