China
Africa
Explore chapters and articles related to this topic
Naturally Occurring Alkaloids with Anti-HIV Activity
Published in Namrita Lall, Medicinal Plants for Cosmetics, Health and Diseases, 2022
Furthermore, the RNase H function associated with HIV-1 RT was about 100-fold less sensitive to the inhibitor than was the RNA-dependent DNA polymerase activity (IC50, 207 μM). On the other hand, the IC50 value for the HIV-2 RT associated RNA-dependent DNA polymerase activity (with poly[rA]n.oligo[dT]12–18 as template primer) was found to be 6.44 μM. However, the inhibition of DNA-dependent DNA polymerase of HIV-2 RT with activated DNA was only slightly weaker (IC50, 9.84 μM). As in the case of HIV-1 RT, again 82 was found to be less effective (IC50, 98 μM) in inhibiting RNase H function (Loya et al., 1994).
Gene Therapy and Small Molecules Used in the Treatment of Cystic Fibrosis
Published in Yashwant Pathak, Gene Delivery, 2022
Manish P. Patel, Uma G. Daryai, Mansi N. Athalye, Praful D. Bharadia, Jayvadan Patel
Since the CFTR gene mutation causes hyperactivation of the epithelial sodium channel (ENaC), the absorption of Na+ ions is enhanced and the lung airway mucus becomes dehydrated. Hence, the inhibition of ENaC expression could serve as a promising therapeutic approach for the treatment of cystic fibrosis. One method for the inhibiting the expression of ENaC-encoding genes (SCNN1A, SCNN1B, SCNN1G, and SCNN1D encoding α, β, γ, and δ ENaC subunits, respectively) involves the use of a single strand nucleic acid known as antisense oligonucleotide (ASO) (Almughem et al., 2020). When this oligonucleotide is hybridized to mRNA, RNase H is triggered to slice the hybridized mRNA. Targeting the α-subunit of ENaC in the respiratory organ, using ASO might inhibit the cationic channel activity (Almughem et al., 2020). Another study showed the possibility of using aerosolized ENaC antisense oligonucleotide containing wing modifications to inhibit ENaC mRNA in CF-like mice models (Hajj and Whitehead, 2017). This aerosolized ENaC antisense oligonucleotide helped to cure various cystic fibrosis symptoms, like airway hyper-responsiveness and inflammation (Crosby et al., 2017).
Synthetic DNA-Based Compounds for the Prevention of Coronary Restenosis: Current Status and Future Challenges
Published in Eric Wickstrom, Clinical Trials of Genetic Therapy with Antisense DNA and DNA Vectors, 2020
Andrew Zalewski, Yi Shi, John D. Mannion, Femando Roqué
Non-sequence-dependent effects are due to the avid binding of negatively charged oligonucleotides (e.g., phosphorothioate) to proteins. The increase in length and concentration of oligomers appears to enhance nonspecific inhibition (Cazenave et al., 1989; Gao et al., 1992; Guvakova et al., 1995). At higher doses oligonucleotides inhibit RNase H activity, thereby eliminating an important mechanism aiding the inhibition of gene expression by antisense. Longer sequences (28-mer) of phosphorothioate homopolymers of cytidine or thymidine have also demonstrated the ability to interact with extracellular growth factors (e.g., bFGF) and their binding with cell surface receptors (Guvakova et al., 1995). This is consistent with their polyanion structure, thereby reducing cell proliferation in non-sequence-dependent manner in vitro and neointimal formation in the rat model in vivo (Guvakova et al., 1995; Wang et al., 1996).
The roles of epidermal growth factor receptor in viral infections
Published in Growth Factors, 2022
In addition to mAbs and TKIs, RNA interference (RNAi) has been proposed as a novel strategy that targets EGFR using a post-transcriptional gene silencing mechanism. Small interfering RNA (siRNA), a double stranded non-coding RNA with a length of 20–25 base pairs that specifically targets EGFR is designed and synthesised. The siRNA is introduced and loaded onto the RNA-induced silencing complex (RISC) where the strands are separated. The antisense strand hybridises with the complementary mRNA targets which are then cleaved by RNase H enzyme, Argonaute on the RISC. Consequently, gene expression of EGFR is suppressed (Figure 8(c)) (Tian et al. 2021; Bumcrot et al. 2006). A number of studies have revealed that combination therapy of EGFR siRNA with chemotherapy or radiotherapy enhance the anti-tumour effect on cancers like NSCLC, ovarian cancer, and oesophageal cancer, suggesting the clinical potentials of RNAi (G. Chen et al. 2012; Satpathy et al. 2016; Zhang et al. 2015).
Flavonoids and Acid-Hydrolysis derivatives of Neo-Clerodane diterpenes from Teucrium flavum subsp. glaucum as inhibitors of the HIV-1 reverse transcriptase–associated RNase H function
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Benedetta Fois, Angela Corona, Enzo Tramontano, Simona Distinto, Elias Maccioni, Rita Meleddu, Pierluigi Caboni, Costantino Floris, Filippo Cottiglia
Since the neo-clerodane flavuglaucin B was not able to inhibit the RDDP function and apparently it does not contain any functionality able to bind to the RNase H active site coordinating the Mg2+ cofactors, we supposed that this compound might bind an allosteric RT site. In order to verify this hypothesis, it was chosen to perform site-directed mutagenesis, determining the independent impact of several amino acid substitutions on the potency of the compound to inhibit the RNase H function. All the selected aminoacids are localised in the RNase H domain and are potentially crucial for the binding of RNase H function inhibitors. To verify a possible interaction for flavuglaucin B in the allosteric site described by Himmel et al.16, residue V108 was replaced by a phenylalanine in order to reduce the binding available space for the compound. Results showed a slight increase in IC50 when flavuglaucin B was assessed against V108F, compared with the wild type enzyme (Figure 4).
Hyaluronan-based delivery of therapeutic oligonucleotides for treatment of human diseases
Published in Expert Opinion on Drug Delivery, 2019
Steric blockage mechanism of ASOs can be also executed in cytoplasm when acting on mRNA (Figure 1(b)) or microRNA (Figure 1(c)). Steric blocker ASOs were proposed to inhibit translation by disrupting ribosomal assembly at the 5ʹ-cap region of mRNA through hybridizing to it [9]. However, the most successful way of inhibition of mRNA translation by ASOs was found to occur via RNase H dependent mechanism. RNase H is an enzyme that cleaves the RNA strand in DNA:RNA duplex and hence RNase H dependent ASOs should contain at least eight 2ʹ-deoxynucleotides long stretch, which is normally flanked with chemically modified RNA bases to increase affinity and reduce susceptibility to degradation by nucleases (gapmer strategy) [10]. After hybridization to target mRNA by Watson-Crick base pairing, RNase H recognizes the mRNA:DNA duplex and cleaves the mRNA strand (Figure 1(d)) via hydrolysis of internucleotide phosphodiester bond, which is followed by release of the ASO and its binding to a new mRNA molecule. This catalytic mechanism recruiting RNase H greatly amplifies the therapeutic potency of ASOs.