Studies on the synthesis of neamine-dinucleosides and neamine-PNA conjugates and their interaction with RNA

Mei, Hui; Xing, Lei; Cai, Lu; Jin, Hongwei; Zhao, Peng; Yang, Zhenjun; Zhang, Liangren; Zhang, Lihe

doi:10.1016/j.bmcl.2008.09.062

Cited by 19 publications

(20 citation statements)

References 24 publications

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“…52,72–76 In one unique study in the antisense approach, we have conjugated the neamine core 2 (Figure 1) corresponding to rings I and II of neomycin B 1 with the 16-mer PNA 3 targeting HIV-1 TAR RNA (anti-TAR PNA). 75 In the resulting conjugate 4 (Figure 1), the presence of the neamine core not only imparts greater solubility and enhanced cellular uptake of PNA, it also confers a unique metal-ion-independent target specific RNA cleavage property to the conjugate.…”

Section: Introductionmentioning

confidence: 99%

A Peptide Nucleic Acid–Aminosugar Conjugate Targeting Transactivation Response Element of HIV-1 RNA Genome Shows a High Bioavailability in Human Cells and Strongly Inhibits Tat-Mediated Transactivation of HIV-1 Transcription

et al. 2012

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The 6-aminoglucosamine ring of the aminoglycoside antibiotic neomycin B (ring II) was conjugated to a 16 mer peptide nucleic acid (PNA) targeting HIV-1 TAR RNA. For this purpose we prepared the aminoglucosamine monomer 15 and attached it to the protected PNA prior to its cleavage from the solid support. We found that the resulting PNA-aminoglucosamine conjugate is stable under acidic condition, efficiently taken up by the human cells and fairly distributed in both cytosol and nucleus without endosomal entrapment since co-treatment with endosome-disrupting agent had no effect on its cellular distribution. The conjugate displayed very high target specificity in vitro and strongly inhibited Tat mediated transactivation of HIV-1 LTR transcription in cell culture system. The unique properties of this new class of PNA conjugate suggest it to be a potential candidate for therapeutic application.

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Section: Introductionmentioning

confidence: 99%

A Peptide Nucleic Acid–Aminosugar Conjugate Targeting Transactivation Response Element of HIV-1 RNA Genome Shows a High Bioavailability in Human Cells and Strongly Inhibits Tat-Mediated Transactivation of HIV-1 Transcription

et al. 2012

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“…In the antisense approach developed to target, for example, messager RNA sequences by hybridization and to inhibit the corresponding translation, conjugates of AGs (NEO, NEA, PARA, ribostamycin and methyl neobiosamine) to oligo-2′-deoxyribonucleotides (ODNs) were synthesized in order to allow the ODN cellular uptake [ 137 , 138 , 139 , 140 , 141 , 142 ]. However, in the resulting conjugates, the strong binding of AGs to the ODN through intramolecular charge–charge interaction between the protonated AG core and the phosphodiester backbone can disturb the selective binding to the RNA target.…”

Section: Other Biological Activities Of Aagsmentioning

confidence: 99%

“…The resulting AAG conjugates should be more soluble in water than the PNAs, and the conjugation could allow an efficient cellular uptake of the PNAs. Therefore, chemical methods for the conjugation of PNAs to AGs have been developed [ 142 , 146 , 147 , 148 , 149 , 150 ]. We conjugated the NEA core with a 16-mer PNA targeting HIV-1 TAR RNA (anti-TAR PNA) [ 146 ].…”

Section: Other Biological Activities Of Aagsmentioning

confidence: 99%

Amphiphilic Aminoglycosides as Medicinal Agents

Dezanet

Kempf

Mingeot‐Leclercq

et al. 2020

IJMS

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The conjugation of hydrophobic group(s) to the polycationic hydrophilic core of the antibiotic drugs aminoglycosides (AGs), targeting ribosomal RNA, has led to the development of amphiphilic aminoglycosides (AAGs). These drugs exhibit numerous biological effects, including good antibacterial effects against susceptible and multidrug-resistant bacteria due to the targeting of bacterial membranes. In the first part of this review, we summarize our work in identifying and developing broad-spectrum antibacterial AAGs that constitute a new class of antibiotic agents acting on bacterial membranes. The target-shift strongly improves antibiotic activity against bacterial strains that are resistant to the parent AG drugs and to antibiotic drugs of other classes, and renders the emergence of resistant Pseudomonas aeruginosa strains highly difficult. Structure–activity and structure–eukaryotic cytotoxicity relationships, specificity and barriers that need to be crossed in their development as antibacterial agents are delineated, with a focus on their targets in membranes, lipopolysaccharides (LPS) and cardiolipin (CL), and the corresponding mode of action against Gram-negative bacteria. At the end of the first part, we summarize the other recent advances in the field of antibacterial AAGs, mainly published since 2016, with an emphasis on the emerging AAGs which are made of an AG core conjugated to an adjuvant or an antibiotic drug of another class (antibiotic hybrids). In the second part, we briefly illustrate other biological and biochemical effects of AAGs, i.e., their antifungal activity, their use as delivery vehicles of nucleic acids, of short peptide (polyamide) nucleic acids (PNAs) and of drugs, as well as their ability to cleave DNA at abasic sites and to inhibit the functioning of connexin hemichannels. Finally, we discuss some aspects of structure–activity relationships in order to explain and improve the target selectivity of AAGs.

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“…For example, a series of synthesized compounds, including β-carboline-nucleoside, neamine-nucleoside conjugates [83,84], neamine-dinucleosides, and neamine-PNA conjugates [85,86], were investigated for their interactions with the corresponding RNA targets. AutoDock 3.0 program was tried at that time, although the updated DOCK 6 program [87] seems to have the optimized parameters and more suitable scoring functions for RNA docking.…”

Section: Molecular Docking On Rnamentioning

confidence: 99%