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Applied and Environmental Microbiology Jan 2021Much of virus fate, both in the environment and in physical/chemical treatment, is dependent on electrostatic interactions. Developing an accurate means of predicting... (Review)
Review
Much of virus fate, both in the environment and in physical/chemical treatment, is dependent on electrostatic interactions. Developing an accurate means of predicting virion isoelectric point (pI) would help to understand and anticipate virus fate and transport, especially for viruses that are not readily propagated in the lab. One simple approach to predicting pI estimates the pH at which the sum of charges from ionizable amino acids in capsid proteins approaches zero. However, predicted pIs based on capsid charges frequently deviate by several pH units from empirically measured pIs. Recently, the discrepancy between empirical and predicted pI was attributed to the electrostatic neutralization of predictable polynucleotide-binding regions (PBRs) of the capsid interior. In this paper, we review models presupposing (i) the influence of the viral polynucleotide on surface charge or (ii) the contribution of only exterior residues to surface charge. We then compare these models to the approach of excluding only PBRs and hypothesize a conceptual electrostatic model that aligns with this approach. The PBR exclusion method outperformed methods based on three-dimensional (3D) structure and accounted for major discrepancies in predicted pIs without adversely affecting pI prediction for a diverse range of viruses. In addition, the PBR exclusion method was determined to be the best available method for predicting virus pI, since (i) PBRs are predicted independently of the impact on pI, (ii) PBR prediction relies on proteome sequences rather than detailed structural models, and (iii) PBR exclusion was successfully demonstrated on a diverse set of viruses. These models apply to nonenveloped viruses only. A similar model for enveloped viruses is complicated by a lack of data on enveloped virus pI, as well as uncertainties regarding the influence of the phospholipid envelope on charge and ion gradients.
Topics: Isoelectric Point; Models, Biological; Polynucleotides; Static Electricity; Viruses
PubMed: 33188001
DOI: 10.1128/AEM.02319-20 -
Biochimie Feb 2018Therapeutic molecules can be classified as low-, middle- and high-molecular weight drugs depending on their molecular masses. Antibodies represent high-molecular weight... (Review)
Review
Therapeutic molecules can be classified as low-, middle- and high-molecular weight drugs depending on their molecular masses. Antibodies represent high-molecular weight drugs and their clinical applications have been developing rapidly. Aptamers, on the other hand, are middle-molecular weight molecules that are short, single-stranded nucleic acid sequences that are selected in vitro from large oligonucleotide libraries based on their high affinity to a target molecule. Hence, aptamers can be thought of as a nucleic acid analog to antibodies. However, several viewpoints hold that the potential of aptamers arises from interesting characteristics that are distinct from, or in some cases, superior to those of antibodies. Recently, therapeutic middle molecules gain considerable attention as protein-protein interaction (PPI) inhibitors. This review summarizes the recent achievements in aptamer development in our laboratory in terms of PPI and non-PPI inhibitors.
Topics: Animals; Aptamers, Nucleotide; Humans
PubMed: 29050945
DOI: 10.1016/j.biochi.2017.10.006 -
European Journal of Pharmaceutical... May 2017This review is a comprehensive analysis of the progress made so far on the delivery of polynucleotide-based therapeutics to the eye, using synthetic nanocarriers.... (Review)
Review
This review is a comprehensive analysis of the progress made so far on the delivery of polynucleotide-based therapeutics to the eye, using synthetic nanocarriers. Attention has been addressed to the capacity of different nanocarriers for the specific delivery of polynucleotides to both, the anterior and posterior segments of the eye, with emphasis on their ability to (i) improve the transport of polynucleotides across the different eye barriers; (ii) promote their intracellular penetration into the target cells; (iii) protect them against degradation and, (iv) deliver them in a long-term fashion way. Overall, the conclusion is that despite the advantages that nanotechnology may offer to the area of ocular polynucleotide-based therapies (especially AS-ODN and siRNA delivery), the knowledge disclosed so far is still limited. This fact underlines the necessity of more fundamental and product-oriented research for making the way of the said nanotherapies towards clinical translation.
Topics: Administration, Ophthalmic; Animals; Drug Carriers; Eye Diseases; Genetic Therapy; Humans; Intravitreal Injections; Nanoparticles; Oligonucleotides, Antisense; Particle Size; Polynucleotides; RNA, Small Interfering; Surface Properties
PubMed: 28263915
DOI: 10.1016/j.ejps.2017.03.001 -
Future Medicinal Chemistry 2015In the field of oligonucleotide drugs, the attachment of PEG is a well-established strategy to prevent enzymatic degradation and avoid renal elimination. Pegaptanib and... (Review)
Review
In the field of oligonucleotide drugs, the attachment of PEG is a well-established strategy to prevent enzymatic degradation and avoid renal elimination. Pegaptanib and other oligonucleotides in clinical development utilize the attachment of linear or branched high molecular weight PEG chains for increase of accumulation and duration of the effect after local or systemic application. The length of PEG chains is decisive for the pharmacokinetic and pharmacodynamic effects. Longer chains increase circulation times, but generally decrease gene-silencing efficiencies for antisense and siRNA agents and binding affinities for aptamers. Shorter chains are less efficient in preventing renal filtration, but have also less impact on the gene-silencing machinery and binding kinetics.
Topics: Animals; Aptamers, Nucleotide; Drug Discovery; Humans; Oligonucleotides; Oligonucleotides, Antisense; Polyethylene Glycols; RNA, Small Interfering
PubMed: 26465713
DOI: 10.4155/fmc.15.94 -
Cell Transplantation 2023Aptamers are single-stranded nucleic acids (DNA, short RNA, or other artificial molecules) produced by the Systematic Evolution of Ligands by Exponential Enrichment... (Review)
Review
Aptamers are single-stranded nucleic acids (DNA, short RNA, or other artificial molecules) produced by the Systematic Evolution of Ligands by Exponential Enrichment (SELEX) technology, which can be tightly and specifically combined with desired targets. As a comparable alternative to antibodies, aptamers have many advantages over traditional antibodies such as a strong chemical stability and rapid bulk production. In addition, aptamers can bind targets in various ways, and are not limited like the antigen-antibody combination. Studies have shown that aptamers have tremendous potential to diagnose and treat clinical diseases. However, only a few aptamer-based drugs have been used because of limitations of the aptamers and SELEX technology. To promote the development and applications of aptamers, we present a review of the methods optimizing the SELEX technology and modifying aptamers to boost the selection success rate and improve aptamer characteristics. In addition, we review the application of aptamers to treat bone diseases.
Topics: Humans; Aptamers, Nucleotide; SELEX Aptamer Technique; Ligands; Bone Diseases
PubMed: 36591965
DOI: 10.1177/09636897221144949 -
Methods in Molecular Biology (Clifton,... 2016
Topics: Animals; Aptamers, Nucleotide; Humans; Protein Binding; SELEX Aptamer Technique
PubMed: 26866065
DOI: No ID Found -
Methods in Molecular Biology (Clifton,... 2017Modifications at either end, both ends, or in-between the ends of a Morpholino oligo provide functional groups for further conjugation. Amino groups are the most useful... (Review)
Review
Modifications at either end, both ends, or in-between the ends of a Morpholino oligo provide functional groups for further conjugation. Amino groups are the most useful and efficient reactive entities for chemical bonding with other molecules. The combination of modifications at both ends, especially with double functionalization at the 3'-end, yields myriad opportunities for diverse applications. An orthogonally protected diamine for advanced 3'-end double modification on the solid phase synthesis support allows the convenient assembly of a vast variety of custom-designed molecules. A particular application is the assembly of a class of Vis-Vivo-Morpholino where at the 3'-end an optically visible fluorophore is installed at one side for fluorescent detection and an in vivo delivery moiety is attached at the other side for intracellular activity studies.
Topics: Amines; Animals; Humans; Morpholinos; Oligonucleotides, Antisense; Solid-Phase Synthesis Techniques
PubMed: 28364232
DOI: 10.1007/978-1-4939-6817-6_4 -
Cells Sep 2023The potential of oligonucleotide therapeutics is undeniable as more than 15 drugs have been approved to treat various diseases in the liver, central nervous system... (Review)
Review
The potential of oligonucleotide therapeutics is undeniable as more than 15 drugs have been approved to treat various diseases in the liver, central nervous system (CNS), and muscles. However, achieving effective delivery of oligonucleotide therapeutics to specific tissues still remains a major challenge, limiting their widespread use. Chemical modifications play a crucial role to overcome biological barriers to enable efficient oligonucleotide delivery to the tissues/cells of interest. They provide oligonucleotide metabolic stability and confer favourable pharmacokinetic/pharmacodynamic properties. This review focuses on the various chemical approaches implicated in mitigating the delivery problem of oligonucleotides and their limitations. It highlights the importance of linkers in designing oligonucleotide conjugates and discusses their potential role in escaping the endosomal barrier, a bottleneck in the development of oligonucleotide therapeutics.
Topics: Endosomes; Central Nervous System; Liver; Muscles; Oligonucleotides
PubMed: 37759475
DOI: 10.3390/cells12182253 -
Analytical and Bioanalytical Chemistry Jan 2015To improve selectivity during sample pretreatment, various selective tools inducing a molecular recognition mechanism during the extraction procedure have been... (Review)
Review
To improve selectivity during sample pretreatment, various selective tools inducing a molecular recognition mechanism during the extraction procedure have been developed, such as sorbents constituted of immobilized antibodies, i.e., immunosorbents, or molecularly imprinted polymers. More recently, as an alternative to both previous approaches, aptamers immobilized onto a solid support, i.e., oligosorbents, were proposed. Thanks to the high affinity and high selectivity of the interaction that some aptamers offer toward some target analytes, they also provide powerful techniques that make selective extraction and the concentration of a target analyte from liquid matrices in one step or sample purification of extracts from solid matrices possible. This review describes the development and the properties of these oligosorbents developed for different types of targets-pharmaceuticals, mycotoxins, proteins, cells, etc. After describing the immobilization procedures, we discuss different parameters characterizing the potential of aptamer-based supports as extraction sorbents. Close relations exist between extraction recoveries and the affinity and amounts of aptamers immobilized on the extraction device. In addition, analyte-aptamer interactions may be affected by matrix components and by additives in the samples. This may also lower extraction recoveries and affect the stability and the possible reusability of the aptamer-based sorbent. All these points are discussed and illustrated. Numerous examples of applications of these sorbents to the treatment of complex samples such as food samples, environmental samples, and biological fluids are also reported. Their association with analytical devices, from conventional to miniaturized analytical systems, is also discussed.
Topics: Aptamers, Nucleotide; Chemistry Techniques, Analytical; Immobilized Nucleic Acids; Miniaturization; Molecular Probes; Solid Phase Extraction
PubMed: 25286873
DOI: 10.1007/s00216-014-8129-5 -
Methods in Molecular Biology (Clifton,... 2022During the last decade, therapeutic oligonucleotide drugs (OND) have witnessed a tremendous development in chemistry and mechanistic understanding that have translated...
During the last decade, therapeutic oligonucleotide drugs (OND) have witnessed a tremendous development in chemistry and mechanistic understanding that have translated into successful clinical applications. Depending on the specific OND mechanism, chemistry, and design, the DMPK and toxicity properties can vary significantly between different OND classes and delivery approaches, the latter including lipid formulations or conjugation approaches to enhance productive OND uptake. At the same time, with the only difference between compounds being the nucleobase sequence, ONDs with same mechanism of action, chemistry, and design show relatively consistent behavior, allowing certain extrapolations between compounds within an OND class. This chapter provides a summary of the most common toxicities, the improved mechanistic understanding and the safety assessment activities performed for therapeutic oligonucleotides during the drug discovery and development process. Several of the considerations described for therapeutic applications should also be of value for the scientists mainly using oligonucleotides as research tools to explore various biological processes.
Topics: Drug Discovery; Oligonucleotides; Oligonucleotides, Antisense
PubMed: 35213031
DOI: 10.1007/978-1-0716-2010-6_25