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Chemical structures of the three representative classes of aminoglycosides and their substitution sites. The central scaffold 2-deoxystreptamine (2-DOS) is ring II.
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RNA is increasingly recognized for its significant functions in biological systems and has recently become an important molecular target for therapeutics development. Aminoglycosides, a large class of clinically significant antibiotics, exert their biological functions by binding to prokaryotic ribosomal RNA (rRNA) and interfering with protein tran...
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... signifi cant aminoglycosides include both naturally occurring drugs and some semi-synthetic derivatives, all of which have a highly-conserved aminocyclitol ring (ring II, Figure 1), a central scaffold that is linked to various aminosugar moi- eties. 13,14 The aminocyclitol ring is comprised primarily of 2-deoxystreptamine (2-DOS) and has 1,3-diamino functionality and three or four hydroxyl groups that provide anchoring points for aminosugars. ...
Context 2
... moi- eties. 13,14 The aminocyclitol ring is comprised primarily of 2-deoxystreptamine (2-DOS) and has 1,3-diamino functionality and three or four hydroxyl groups that provide anchoring points for aminosugars. Aminoglycosides can be divided into 3 subclasses depending on the substitution pattern: 4-monosubsituted, or 4,5-or 4,6- disubsituted ( Fig. 1). Aminoglycosides in each subclass show close structural resemblance. Although 2-deoxystreptamine or 2-deoxy-myo-inosa- 1,3-diamine is actually derived from D-glucose-6- phosphate biosynthetically, the numbering system is based on streptamine's biogenic precursor myo- inositol as described by Fletcher. 15 Neamine, paromamine, and ...
Citations
... According to the carbon substitution position, aminoglycosides can be classified into mono-substituted aminoglycosides (substitution at C4 position, referring to ring I) and di-substituted ones (substitution at both the C4 and C5 positions or at both the C4 and C6 positions). The substituent at the C5 or C6 positions of the 2-DOS is referred to as ring III [54] (Figure 6). ...
... According to the carbon substitution position sides can be classified into mono-substituted aminoglycosides (substitution referring to ring I) and di-substituted ones (substitution at both the C4 and or at both the C4 and C6 positions). The substituent at the C5 or C6 position is referred to as ring III [54] (Figure 6). ...
Nonsense mutations that generate a premature termination codon (PTC) can induce both the accelerated degradation of mutated mRNA compared with the wild type version of the mRNA or the production of a truncated protein. One of the considered therapeutic strategies to bypass PTCs is their “readthrough” based on small-molecule drugs. These molecules promote the incorporation of a near-cognate tRNA at the PTC position through the native polypeptide chain. In this review, we detailed the various existing strategies organized according to pharmacological molecule types through their different mechanisms. The positive results that followed readthrough molecule testing in multiple neuromuscular disorder models indicate the potential of this approach in peripheral neuropathies.
... All members of this group bind to rRNA and 30s ribomes within the protein; however, interaction and binding differ depending on the chemical structure of the drug. Members of the aminoglycoside group with a 2-deoxystreptamine (2-DOS) core, such as gentamicin, sisomicin, kanamycin, and tobramycin, are particularly effective against many gram-negative bacterial pathogens [6][7][8]. This class of aminoglycosides is substituted at the positions 4 (ring I) and 6 (ring III) of the 2-DOS core (ring II) by the aminomodified sugars, and these substituents are called primary and double primary rings, respectively: ...
... Sisomicin is a broad-spectrum aminoglycoside antibiotic and is structurally similar to gentamicin but has a unique unsaturated diamino sugar ring. Among aminoglycoside antibiotics, sisomicin has the highest activity against gram-positive bacteria [7,8]. ...
Quantum chemical modeling and full geometry optimization of sisomicin and gentamicin was carried out by the correlation functional B3LYP using augmented with polarization functions for heavy atoms 6-311G(d) and Dunning’s correlation consistent cc-pVDZ basis sets. The effect of the basis set on the calculation results of molecular structure and quantum chemical descriptors of the titled compounds was studied. Special attention was paid to the intramolecular NH…N, OH…N, OH…O, NH…O hydrogen bonds in sisomicin and gentamicin. According to theoretical calculations, the distances between hydrogen and acceptor atoms are slightly larger than a typical length due to a significant deviation of the intramolecular H-bonds from a linearity. To evaluate the extent of electron density delocalization from the lone pairs of atoms into the antibonding neighboring orbitals and inside H-bonds within the systems, NBO (Natural Bond Orbital) analysis was used at two levels of theory. The most intensive interactions between electron donor and electron acceptor in the structures under consideration were determined and their delocalization energies were evaluated. Based on the obtained data, classical electrostatic nature of the weak H-bonds and conjugation effects stabilizing the molecules were suggested
... The numerous functional and structural proteins possessed by SARS-CoV-2 could be essential targets for inhibition, sensing, and diagnosis. Likewise, the singlestranded RNA genome is another key target for viral testing [55][56][57], which could equally help in testing for COVID-19. These sensing systems have shown significant effects in detecting the COVID-19-RNA at a minimal concentration within a short period, and this could be advantageous over Real-Time Polymerase Chain Reaction (qRT-PCR) testing because nucleic acid-based sensing is handier and more economical than qRT-PCR. ...
Abstract: There is an urgent need to address the global mortality of the COVID-19 pandemic, as
it reached 6.3 million as of July 2022. As such, the experts recommended the mass diagnosis of
SARS-CoV-2 infection at an early stage using nanotechnology-based sensitive diagnostic approaches.
The development of nanobiosensors for Point-of-Care (POC) sampling of COVID-19 could ensure
mass detection without the need for sophisticated laboratories or expert personnel. The use of
Artificial Intelligence (AI) techniques for POC detection was also proposed. In addition, the utilization
of various antiviral nanomaterials such as Silver Nanoparticles (AgNPs) for the development of
masks for personal protection mitigates viral transmission. Nowadays, nano-assisted vaccines have
been approved for emergency use, but their safety and effectiveness in the mutant strain of the
SARS-CoV-2 virus remain challenging. Methodology: Updated literature was sourced from various
research indexing databases such as PubMed, SCOPUS, Science Direct, Research Gate and Google
Scholars. Result: We presented the concept of novel nanotechnology researched discovery, including
nano-devices, electrochemical biosensing, nano-assisted vaccine, and nanomedicines, for use in recent
times, which could be a formidable step for future management of COVID-19
... Antisense oligonucleotides represent the most established entities and while possessing high affinity and selectivity they tend to suffer from delivery issues (71). Alternative approaches to target RNA make use of extended or multivalent ligands derived from large-scale screening approaches or from natural products such as aminoglycosides (72)(73)(74). However, these approaches involve complicated development processes since only limited structural information is available. ...
The design of high-affinity, RNA-binding ligands has proven very challenging. This is due to the unique structural properties of RNA, often characterized by polar surfaces and high flexibility. In addition, the frequent lack of well-defined binding pockets complicates the development of small molecule binders. This has triggered the search for alternative scaffolds of intermediate size. Among these, peptide-derived molecules represent appealing entities as they can mimic structural features also present in RNA-binding proteins. However, the application of peptidic RNA-targeting ligands is hampered by a lack of design principles and their inherently low bio-stability. Here, the structure-based design of constrained ␣-helical peptides derived from the viral suppressor of RNA silencing, TAV2b, is described. We observe that the introduction of two inter-side chain crosslinks provides peptides with increased ␣-helicity and protease stability. One of these modified peptides (B3) shows high affinity for double-stranded RNA structures including a palindromic siRNA as well as microRNA-21 and its precursor pre-miR-21. Notably, B3 binding to pre-miR-21 inhibits Dicer processing in a biochemical assay. As a further characteristic this peptide also exhibits cellular entry. Our findings show that constrained peptides can efficiently mimic RNA-binding proteins rendering them potentially useful for the design of bioactive RNA-targeting ligands.
... The chemical structures of different types of aminoglycosides are given in Fig. 1. The polycationic nature causes aminoglycosides to target the negatively charged nucleic acid of bacterial cells as the major site of bactericidal action (Chittapragada et al. 2009). By interacting with the outer membrane and utilizing the energy-dependent phase I, aminoglycosides arrive at the protein synthesis system in the bacterial cellular cytosol (Taber et al. 1987). ...
Aminoglycosides are one of the common classes of antibiotics that have been widely used for treating infections caused by pathogenic bacteria. The mechanism of bactericidal action by aminoglycosides is well-known, by which it terminates the cytoplasmic protein synthesis. However, the potentials of aminoglycosides become hindered when facing the evolution of bacterial resistance mechanisms. Among multiple resistance mechanisms displayed by bacteria against antibiotics, the formation of biofilm is the mechanism that provides a barrier for antibiotics to reach the cellular level. Bacteria present in the biofilm also get protection against the impact of host immune responses, harsh environmental conditions, and other antimicrobial treatments. Hence, with the multifaceted resistance developed by biofilm-forming pathogenic bacteria, antibiotics are therefore discontinued for further applications. However, the recent research developed several alternative strategies such as optimization of the active concentration, modification of the environmental conditions, modification of the chemical structure, combinatorial application with other active agents, and formulation with biocompatible carrier materials to revitalize and exploit the new potential of aminoglycosides. The present review article describes the above mentioned multiple approaches and possible mechanisms for the application of aminoglycosides to treat biofilm-associated infections.
... 4,5 Much of the chemical diversity is derived from alternative decoration of the sugar moieties. Examples of 4,6-disubstituted AGs include amikacin, kanamycin and tobramycin 6 (Figure 1a). ...
... 4 ANTs modify their target through adenylylation, attaching an adenosine monophosphate to a hydroxyl group on one of the amino sugars or the 2-DOS core of the AG substrate. ANTs are categorized based on the substrate position modified through adenylylation and to date nine ANT enzymes have been discovered, leading to the delineation of five classes: ANT(2 00 ), ANT(3 00 ), ANT(4 0 ), ANT (6), and ANT (9). 4 Further categorization based on the resistance profile conferred as well as sequence variation has identified additional subclasses of these enzymes. ...
Aminoglycosides were one of the first classes of broad‐spectrum antibacterial drugs clinically used to effectively combat infections. The rise of resistance to these drugs, mediated by enzymatic modification, has since compromised their utility as a treatment option, prompting intensive research into the molecular function of resistance enzymes. Here, we report the crystal structure of aminoglycoside nucleotidyltransferase ANT(4′)‐IIb in apo and tobramycin‐bound forms at a resolution of 1.6 and 2.15 Å, respectively. ANT(4′)‐IIb was discovered in the opportunistic pathogen Pseudomonas aeruginosa and conferred resistance to amikacin and tobramycin. Analysis of the ANT(4′)‐IIb structures revealed a two‐domain organization featuring a mixed β‐sheet and an α‐helical bundle. ANT(4′)‐IIb monomers form a dimer required for its enzymatic activity, as coordination of the aminoglycoside substrate relies on residues contributed by both monomers. Despite harbouring appreciable primary sequence diversity compared to previously characterized homologues, the ANT(4′)‐IIb structure demonstrates a surprising level of structural conservation highlighting the high plasticity of this general protein fold. Site‐directed mutagenesis of active site residues and kinetic analysis provides support for a catalytic mechanism similar to those of other nucleotidyltransferases. Using the molecular insights provided into this ANT(4′)‐IIb‐represented enzymatic group, we provide a hypothesis for the potential evolutionary origin of these aminoglycoside resistance determinants.
... Aminoglycosides such as kanamycin and gentamicin are conformationally flexible enough to bind to a variety of RNAs (ribosomal A-site, HIV TAR, HIV RRE, Group I intron, RNase P, tmRNA, the eukaryotic A site), but it is known that there are RNA-sequence and RNA structuredependent elements that are required for aminoglycoside binding. 28 Such features may be lacking in our target set. ...
Although the potential value of RNA as a target for new small molecule therapeutics is becoming increasingly credible, the physicochemical properties required for small molecules to selectively bind to RNA remain relatively unexplored. To investigate the druggability of RNAs with small molecules, we have employed affinity mass spectrometry, using the Automated Ligand Identification System (ALIS), to screen 42 RNAs from a variety of RNA classes, each against an array of chemically diverse drug-like small molecules (~50,000 compounds) and functionally annotated tool compounds (~5100 compounds). The set of RNA–small molecule interactions that was generated was compared with that for protein–small molecule interactions, and naïve Bayesian models were constructed to determine the types of specific chemical properties that bias small molecules toward binding to RNA. This set of RNA-selective chemical features was then used to build an RNA-focused set of ~3800 small molecules that demonstrated increased propensity toward binding the RNA target set. In addition, the data provide an overview of the specific physicochemical properties that help to enable binding to potential RNA targets. This work has increased the understanding of the chemical properties that are involved in small molecule binding to RNA, and the methodology used here is generally applicable to RNA-focused drug discovery efforts.
... A survey of such complexes ( Table 1) reveals common chemical features including: positively charged alkylamine or guanidinium groups, and planar heteroaromatic groups, such as napthyl, indole, phenyl, or phenothiazine moieties. Although neomycin and derivatives thereof are known to bind TAR (92), we will not consider aminoglycosides here, due to their promiscuous RNA binding resulting from many positively charged amines (Fig. 3A), their toxicity (86,(93)(94)(95), and the recent focus on compounds with "drug-like" properties in terms of potency, solubility, selectivity, and distribution, as well as RNA targeting by use of specific modes of molecular recognition [reviewed in (96)]. ...
Small molecules and short peptides that potently and selectively bind RNA are rare, making the molecular structures of these complexes highly exceptional. Accordingly, several recent investigations have provided unprecedented structural insights into how peptides and proteins recognize the HIV-1 trans-activation response (TAR) element, a 59-nucleotide long, noncoding RNA segment in the 5'-long terminal repeat region of viral transcripts. Here we offer an integrated perspective on these advances by describing earlier progress on TAR-binding to small molecules, and by drawing parallels to recent successes in the identification of compounds that target the hepatitis C virus internal ribosome entry site (IRES) and the flavin-mononucleotide riboswitch. We relate this work to recent progress that pinpoints specific determinants of TAR recognition by: (i) viral Tat proteins, (ii) an innovative lab-evolved TAR-binding protein and (iii) an ultrahigh-affinity cyclic peptide. New structural details are used to model the TAR-Tat-super elongation complex (SEC) that is essential for efficient viral transcription and represents a focal point for antiviral drug design. A key prediction is that the Tat transactivation domain makes modest contacts with the TAR apical loop, whereas its arginine-rich motif (ARM) spans the entire length of the TAR major groove. This expansive interface has significant implications for drug discovery and design, and further suggests that future lab-evolved proteins could be deployed to discover steric restriction points that block Tat-mediated recruitment of the host SEC to HIV-1 TAR.
... [36][37][38][39] AGs have binding capabilities with many different functional RNAs and have become a central focus in an effort to understand the underlying principles of RNA recognition by small molecules. [40][41][42][43][44][45][46][47] In view of AG structure characteristics and binding capabilities with different functional RNAs, we surmised that AGs might be used as a nonionic, biocompatible, biodegradable delivery vector for the AO PMO by forming a stable complex for the treatment of muscular dystrophy. We chose to investigate a few AGs that are commercially available and have been widely used as biomaterials. ...
Antisense oligonucleotide (AO)therapy has been the specific treatment for Duchenne muscular dystrophy, with ongoing clinical trials. However, therapeutic applications of AOs remain limited, particularly because of the lack of efficient cellular delivery methods imperative for achieving efficacy. In this study, we investigated a few aminoglycosides (AGs)for their potential to improve the delivery of antisense phosphorodiamidate morpholino oligomer (PMO)both in vitro and in vivo. AGs had lower cytotoxicity compared with Endoporter, the currently most effective delivery reagent for PMO in vitro, and improved efficiency in PMO delivery 9- to 15-fold over PMO alone. Significant enhancement in systemic PMO-targeted dystrophin exon 23 skipping was observed in mdx mice, up to a 6-fold increase with AG3 (kanamycin)and AG7 (sisomicin)compared with PMO only. No muscle damage could be detected clearly with the test dosages. These results establish AGs as PMO delivery-enhancing agents for treating muscular dystrophy or other diseases.
... A fragment-based screening approach to identify ligands of the HIV TAR has been described by Göbel and colleagues, who interrogated a set of 29 small molecules that were selected to represent molecular motifs beneficial for RNA recognition 119 . Also, Benhida and coworkers pursued a design approach for TAR RNA-binding ligands based on aminophenylthiazole derivatives 54,159 . More recently, Schneekloth and colleagues have applied small molecule microarray (SMM) screening of a fluorescently labeled TAR hairpin to identify selective chemotypes (Fig. 2D) 54 . ...
The increasing appreciation for the crucial roles of RNAs in infectious and non-infectious human diseases makesthem attractive therapeutic targets. Coding and non-coding RNAs frequently fold into complex conformations which, if effectively targeted, offer opportunities to therapeutically modulate numerous cellular processes, including those linked to undruggable protein targets. Despite the considerable skepticism as to whether RNAs can be targeted with small molecule therapeutics, overwhelming evidence suggests the challenges we are currently facing are not outside the realm of possibility. In this review, we highlight the most recent advances in molecular techniques that have sparked a revolution in understanding the RNA structure-to-function relationship. We bring attention tothe application of these modern techniques to identify druggable RNA targets and to assess small molecule binding specificity. Finally, we discuss novel screening methodologies that support RNA drug discovery and present examples of therapeutically valuable RNA targets.
