Review ArticleAdvances in the delivery of antisense oligonucleotides for combating bacterial infectious diseases
Section snippets
Advantages of antisense antibacterial agents
Compared with traditional antibiotics, ASOs-based antibacterial agent has many advantages: (1) Easy design: In theory, all the disease-related genes in the clinical pathogenic bacteria can be targeted by ASOs, and the only knowledge necessary for ASO design is the nucleotide sequence. (2) Precise target: ASOs can target their complementary mRNA and selectively prevent the expression of single isoform among a class of closely related genes, which is often difficult to be achieved by traditional
Dilemma of developing antisense antibacterial agents
In spite of remarkable technology progress in the research of RNA-based therapeutics targeting host cells, two main obstacles hinder further development and application of antisense antibacterial agents.
Delivery barriers of antisense antibacterial agents
The successful delivery of ASOs into bacterial cells is much more difficult than into mammalian cells, which has been the key restraint hindering the development of antisense antibacterial agents.49 The reasons behind the difficulty mainly include three aspects:
Current delivery strategies for antisense antibacterial agents
Currently, ASO drugs used in non-infectious diseases, delivered by covalent coupling or non-covalent binding strategy, has made a great breakthrough. However, the development of delivery system for antisense antibacterial agents relatively lags, and most reported data focused on the ASO–cell-penetrating peptide (CPP) conjugation. However, the minimum inhibitory concentrations of ASO–CPP against pathogenic bacteria observed by different labs mostly ranged from 10 to 40 μM, which is much higher
Conclusions
RNA-based therapeutics has made great advancement in the field of cancer, severe and rare genetic disorders, and cardiovascular and metabolic diseases. Several RNA-based drugs discovered by the leading companies, such as Ionis Pharmaceuticals™ and Regulus Therapeutics, Inc., have been researched in clinical phase, which will carry us toward a new stage of antisense antibacterial agents. During the past three decades, the potency of ASOs to inhibit the expression of essential genes, resistant
References (118)
- et al.
In vivo evaluation of candidate allele-specific mutant huntingtin gene silencing antisense oligonucleotides
Mol Ther
(2014) - et al.
"Huntingtin holiday": progress toward an antisense therapy for Huntington's disease
Neuron
(2012) - et al.
Antisense therapy for hepatitis C virus infection
J Hepatol
(2014) - et al.
Cationic liposomal lipids: from gene carriers to cell signaling
Prog Lipid Res
(2008) - et al.
The macrophage paradox
Immunity
(2014) - et al.
The dynamic landscapes of RNA architecture
Cell
(2009) - et al.
Effective intracellular delivery of oligonucleotides in order to make sense of antisense
J Control Release
(2004) - et al.
Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings
Adv Drug Deliv Rev
(2001) - et al.
Current applications of nanoparticles in infectious diseases
J Control Release
(2016) Cell-penetrating peptides: classes, origin, and current landscape
Drug Discov Today
(2012)
Cell penetrating peptide conjugates of steric block oligonucleotides
Adv Drug Deliv Rev
Peptide nucleic acids inhibit growth of Brucella suis in pure culture and in infected murine macrophages
Int J Antimicrob Agents
Antisense inhibition of gene expression and growth in gram-negative bacteria by cell-penetrating peptide conjugates of peptide nucleic acids targeted to rpoD gene
Biomaterials
A peptide-morpholino oligomer conjugate targeting Staphylococcus aureus gyrA mRNA improves healing in an infected mouse cutaneous wound model
Int J Pharm
Optimisation of vectorisation property: A comparative study for a secondary amphipathic peptide
Int J Pharm
A new potent secondary amphipathic cell-penetrating peptide for siRNA delivery into mammalian cells
Mol Ther
A novel penetratin-modified complex for noninvasive intraocular delivery of antisense oligonucleotides
Int J Pharm
Safety profile of the intravenous administration of brain-targeted stable nucleic acid lipid particles
Data Brief
DNA nanostructures as programmable biomolecular scaffolds
Bioconjug Chem
Antibacterial peptide nucleic acid-antimicrobial peptide (PNA-AMP) conjugates: antisense targeting of fatty acid biosynthesis
Bioconjug Chem
Antisense peptide nucleic acid-peptide conjugates for functional analyses of genes in Pseudomonas aeruginosa
Bioorg Med Chem
Antibacterial drug development: challenges, recent developments, and future considerations
Clin Pharmacol Ther
Challenges of antibacterial discovery
Clin Microbiol Rev
ESKAPEing the labyrinth of antibacterial discovery
Nat Rev Drug Discov
Predictive compound accumulation rules yield a broad-spectrum antibiotic
Nature
Drugs for bad bugs: confronting the challenges of antibacterial discovery
Nat Rev Drug Discov
Allele-selective inhibition of mutant Huntingtin with 2-thio- and C5-triazolylphenyl-deoxythymidine-modified antisense oligonucleotides
Nucleic Acid Ther
Allele-specific suppression of mutant huntingtin using antisense oligonucleotides: providing a therapeutic option for all Huntington disease patients
PLoS One
The landscape of antisense gene expression in human cancers
Genome Res
Antisense oligonucleotides in cancer
Curr Opin Oncol
Antiviral effect of hepatitis B virus S/C gene loci antisense locked nucleic acid on transgenic mice in vivo
Genet Mol Res
HIV-1 RNAs: sense and antisense, large mRNAs and small siRNAs and miRNAs
Curr Opin HIV AIDS
Human T-cell leukemia virus type 3 (HTLV-3) and HTLV-4 antisense-transcript-encoded proteins interact and transactivate Jun family-dependent transcription via their atypical bZIP motif
J Virol
Clinical and preclinical pharmacokinetics and pharmacodynamics of mipomersen (kynamro((R))): a second-generation antisense oligonucleotide inhibitor of apolipoprotein B
Clin Pharmacokinet
Alicaforsen, an antisense inhibitor of ICAM-1, as treatment for chronic refractory pouchitis after proctocolectomy: a case series
United European Gastroenterol J
A phase I/IIa clinical trial in duchenne muscular dystrophy using systemically delivered morpholino antisense oligomer to skip exon 53 (SKIP-NMD)
Hum Gene Ther Clin Dev
Progress in therapeutic antisense applications for neuromuscular disorders
Eur J Hum Genet
Bacterial antisense RNAs are mainly the product of transcriptional noise
Sci Adv
Cis-encoded non-coding antisense RNAs in streptococci and other low GC Gram (+) bacterial pathogens
Front Genet
Bacterial antisense RNAs: how many are there, and what are they doing?
Annu Rev Genet
Antisense effects of PNAs in bacteria
Methods Mol Biol
Antibacterial drug discovery in the resistance era
Nature
Antisense antibiotics: a brief review of novel target discovery and delivery
Curr Drug Discov Technol
Antisense RNA regulation and application in the development of novel antibiotics to combat multidrug resistant bacteria
Sci Prog
Designing drugs that overcome antibacterial resistance: where do we stand and what should we do?
Expert Opin Drug Discovery
Targeting bacterial RNA polymerase: promises for future antisense antibiotics development
Infect Disord Drug Targets
In vivo characterization of activatable cell penetrating peptides for targeting protease activity in cancer
Integr Biol (Camb)
Next-generation lipids in RNA interference therapeutics
ACS Nano
Overcoming cellular barriers for RNA therapeutics
Nat Biotechnol
Control of phosphorothioate stereochemistry substantially increases the efficacy of antisense oligonucleotides
Nat Biotechnol
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2022, Journal of Controlled ReleaseCitation Excerpt :While, Intracellular bacterial infection involves membrane-bound compartments, and ASO drugs should penetrate biological membrane barriers to reach the target. In addition to obstacles faced in the extracellular bacterial infection, ASOs have to penetrate deeper biological membrane barriers to accumulate on the bacteria surface and reach sufficient concentration in the pathogenic bacterial cells (Fig. 4) [137]. Good et al. [138] first conjugated antisense PNA to CPP, created a library of Peptide nucleic acid (PNA) cell-penetrating peptide (PNA-CPP) conjugates, and showed that covalent conjugation did not influence the therapeutic efficacy of ASO against bacterial strains.
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2022, Advances in Inorganic ChemistryCitation Excerpt :This occurs by degrading the mRNA or blocking its binding to the ribosome.54,55 The most significant challenge to the therapeutic success of antibacterial oligonucleotides is their delivery to the site of action, which is the interior of the bacterial cell.56 To avoid premature excretion by the kidney and degradation by nucleases present in the blood, nucleotides must be chemically modified.
Competing financial interests: All of the authors declared no competing financial interest.
This work is supported by the National Natural Science Foundation of China (81402975, 81502143, 51675411) and the youth talent cultivation grants of the Fourth Military Medical University.
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These three authors contributed equally to this work.