During the last two decades, the molecular self-assembly of the short peptide diphenylalanine (Phe-Phe) motif has attracted increasing focus due to its unique morphological structure and utility for ...potential applications in biomaterial chemistry, sensors and bioelectronics. Due to the ease of their synthetic modifications and a plethora of available experimental tools, the self-assembly of free and protected diphenylalanine scaffolds (H-Phe-Phe-OH, Boc-Phe-Phe-OH and Boc-Phe-Phe-OMe) has unfurled interesting tubular, vesicular or fibrillar morphologies. Developing on this theme, here we attempt to examine the effect of structure and properties (hydrophobic and H-bonding) modifying the functional C-terminus conjugated substituents on Boc-Phe-Phe on its self-assembly process. The consequent self-sorting due to H-bonding, van der Waals force and π-π interactions, generates monodisperse nano-vesicles from these peptides characterized via their SEM, HRTEM, AFM pictures and DLS experiments. The stability of these vesicles to different external stimuli such as pH and temperature, encapsulation of fluorescent probes inside the vesicles and their release by external trigger are reported. The results point to a new direction in the study and applications of the Phe-Phe motif to rationally engineer new functional nano-architectures.
DNA:bm-PNA duplexes endowed with all-C on either the t-amide or triazole face and mixed base sequence on the other face can be welded with silver ions through C:Ag
:C connects to give triple duplexes ...in one complex. The interplay of WC and Ag
-mediated duplexes leads to synergistic stability effects on both duplexes and the complex.
The replacement of α(CH
) by NH in monomers of standard
PNA and its homologue β-
PNA leads to respective
-PNA monomers (
and
) in which the N
H can form either an 8-membered H-bonded ring with ...folding of the backbone (DMSO and water) or a 5-membered N
H─αCO (water) to stabilize
-type rotamers. Such
-PNA oligomers with exclusive
rotamers and intraresidue backbone H-bonding can modulate its DNA/RNA binding and assembling properties.
Fluorous PNA analogues possessing fluorine as inherent part of aminopropylglycine (apg) backbone (γ-CF2-apg PNA) have been synthesized and evaluated for biophysical and cell penetrating properties. ...These form duplexes of higher thermal stability with cRNA than cDNA, although destabilized compared to duplexes of standard aeg-PNA. Cellular uptake of the fluorinated γ-CF2-apg PNAs in NIH 3T3 and HeLa cells was 2-3-fold higher compared to that of nonfluorinated apg PNA, with NIH 3T3 cells showing better permeability compared to HeLa cells. The backbone fluorinated PNAs, which are first in this class, when combined with other chemical modifications may have potential for future PNA-based antisense agents.
Inherently chiral, cationic am-PNAs having pendant aminomethylene groups at α(R/S) or γ(S) sites on PNA backbone have been synthesized. The modified PNAs are shown to stabilize duplexes with ...complementary cDNA in a regio- and stereo-preferred manner with γ(S)-am PNA superior to α(R/S)-am PNAs and α(R)-am PNA better than the α(S) isomer. The enhanced stabilization of am-PNA:DNA duplexes is accompanied by a greater discrimination of mismatched bases. This seems to be a combined result of both electrostatic interactions and conformational preorganization of backbone favoring the cDNA binding. The am-PNAs are demonstrated to effectively traverse the cell membrane, localize in the nucleus of HeLa cells, and exhibit low toxicity to cells.
Fluorine incorporation into organic molecules imparts favorable physicochemical properties such as lipophilicity, solubility and metabolic stability necessary for drug action. Toward such ...applications using peptide nucleic acids (PNA), we herein report the chemical synthesis of fluorinated PNA monomers and biophysical studies of derived PNA oligomers containing fluorine in in the acetyl side chain (-CHF-CO-) bearing nucleobase uracil (5-F/5-CF3-U). The crystal structures of fluorinated racemic PNA monomers reveal interesting base pairing of enantiomers and packing arrangements directed by the chiral F substituent. Reverse phase HPLC show higher hydrophobicity of fluorinated PNA oligomers, dependent on the number and site of the fluorine substitution: fluorine on carbon adjacent to the carbonyl group induces higher lipophilicity than fluorine on nucleobase or in the backbone. The PNA oligomers containing fluorinated bases form hybrids with cDNA/RNA with slightly lower stability compared to that of unmodified aeg PNA, perhaps due to electronic effects. The uptake of fluorinated homooligomeric PNAs by HeLa cells was as facile as that of nonfluorinated PNA. In conjunction with our previous work on PNAs fluorinated in backbone and at N-terminus, it is evident that the fluorinated PNAs have potential to emerge as a new class of PNA analogues for applications in functional inhibition of RNA.
Molecular self‐assembly of the minimal diphenylalanine (Phe‐Phe) peptide building block shows unique morphological organizations and potential utility in biochemistry and biomaterials applications. ...Furthermore, the molecular engineering of nucleoside‐conjugated Phe‐Phe scaffolds allows the formation of diverse architectures with tunable biophysical properties. While the self‐assembly of homochiral l‐dipeptides is well characterized, stereochemistry is known to determine the conformation, which also governs self‐assembly through molecular packing effects. Here, the effect of stereochemistry and hydrophobicity on Phe‐Phe nucleoside conjugates using all four diastereomers (l)Phe‐(l)Phe, (d)Phe‐(dPhe, (l)Phe‐(d)Phe, and (d)Phe‐(l)Phe of Phe‐Phe conjugates is systematically studied. The homochiral peptides form well‐defined nanorods while the heterochiral dipeptides do not form any regular structures. Since heterocyclic nucleobases can self‐assemble through hydrogen‐bonded complementary base‐pairing, the self‐assembly of chiral nucleoside‐conjugated Phe‐Phe peptides is examined. All conjugated Phe‐Phe peptides form seamless spherical particles. The completely or partially deprotected peptides do not assemble to any defined nanostructures suggesting that self‐assembly is governed by the precise hydrophobic/hydrophilic balance in the assembling units. Contact angle measurements of the diastereomeric peptides reveal a subtle difference in stereochemistry‐dependent molecular hydrophobicity. Taken together, it is revealed that the combination of chirality together with hydrophobic/hydrophilic balance within the peptides dictates the self‐assembly of Phe‐Phe dipeptide nucleoside conjugates.
Nucleoside‐conjugated Phe‐Phe hybrids of different chirality are prepared. The effects of stereochemistry and hydrophobicity in the C‐/N‐termini of Phe‐Phe motif on self‐assembly and the resulting conformational properties are explored. The results indicate nucleoside‐conjugated chiral peptides as a new direction in the study of Phe‐Phe motif to rationally engineer new functional nanostructures involving rational design of short chiral peptide‐based biomaterials.
Branched chiral peptide nucleic acids br(4S/R)-PNA with three arms of PNA-C4 strands were constructed on a central chiral core of 4(R/S)-aminoproline as the branching center. The addition of Ag+ ...triggered the self-assembly of branched PNAs through the formation of C-Ag+-C metallo base pairing of the three PNA C4 arms leading to non-covalent dendrimers, whose architecture is directed by the C4(R/S)-stereocenter of core 4-aminoproline. The 4S-aminoprolyl core enabled the precise formation of four-pointed nanostars that was not realised with 4R-aminoprolyl or acyclic, achiral aminoethyl glycyl PNA cores. The dendritic assembly of 4 pointed nanostars exhibited net chirality of base stacks in CD spectra, while the base stack assembly from br(4R)-PNA 2 was overall achiral. The results demonstrate that the silver assisted, 4S-aminoproline core stereo selective chiral assembly of branched PNAs manifests into nanostar morphology. The chiral branched PNAs open new vistas in the supramolecular organization of nucleic acids.
